Donath–Landsteiner antibodies share similarities with cold agglutinin disease in recognition and connection of the antigens on the red blood cells' surface in the presence of relatively lower temperatures compared to core body temperature. Yet, the place where the hemolysis taking place differentiates between  D-L  antibodies and cold agglutinin. [ 6 ] [ 7 ] [ 8 ]  D-L antibodies rather fix  complement system  which result in  hemolysis in vessels  (intra-vessels).  Blood vessels  are pathways carrying living-required elements to reach everywhere inside the body through circulation. This explains why the clinical manifestations of hemolysis caused by D-L antibodies are in line with representations of  hemoglobinemia  and  hemoglobinuria . D-L antibodies, typically  IgG , are characterized by targeting against red blood cells' on-surface  antigens called "P" . [ 9 ] [ 10 ]


The  pathophysiology  of  Donath–Landsteiner hemolytic anemia  has been entitled as  paroxysmal cold hemoglobinuria . [ citation needed ]


Cryoglobulins are abnormal antibodies that only dissolve/disappear at temperature higher than 37 °C (99 °F) and form solid or gel-like immune complexes in presence of the environment under 37 °C (99 °F), [ 11 ] [ 12 ]  which can block blood vessels and cause a variety of health problems [ 12 ]  including inflammation and organ damage. [ 13 ] [ 14 ]


Many people affected by cryoglobulins will not experience any unusual signs or symptoms. When present, symptoms vary but may include  breathing problems ;  fatigue ;  glomerulonephritis ;  joint pain  or  muscle pain ;  purpura ;  Raynaud's phenomenon ;  skin death ; and/or  skin ulcers . In some cases, the exact underlying cause is unknown; however, cryoglobulinemia can be associated with a variety of conditions including certain types of infection; chronic inflammatory diseases (such as autoimmune disease); and/or cancers of the blood or immune system. Treatment varies based on the severity of the condition, the symptoms present in each person and the underlying cause. [ 12 ]


At least 90% of cases having cryoglobulins in body,  hepatitis C  is to blame, [ 11 ] [ 13 ]  reflecting the importance of preclusion of hepatitis C. [ 11 ] [ 13 ]  The presence of cryoglobulins in body satisfies the criterion of the diagnosis of  cryoglobulinemia , a disease that  inflame the blood vessels  and organs like kidney, nerves, joints, lungs and skin. [ 11 ]  Normally, no cryoglobulins should be found in the body. [ 11 ]


Cryoglobulins more than often do not interact with red blood cells, unless it combines the features of cold agglutinin with cryoglobulins, although the chance is deemed rare.  Therefore, cryoglobulins don't produce hemolysis effect, however its serious  complications  such as  systemic inflammatory  or neoplastic disorders can in turn lead to anemia. [ 13 ]


Although there is some overlap of symptoms, cryoglobulinemia and cold agglutinin disease differ in the process by which blood vessels become blocked. [ 12 ]  In cryoglobulinemia, antibodies accumulate and block blood vessels. [ 12 ] [ 15 ]  In cold agglutinin disease, antibodies (different from those in cryoglobulinemia) attack and kill red blood cells, which then accumulate and  block blood vessels . [ 12 ] [ 16 ]


Common features among the three conditions above include:


Complement activation  plays a definitive but limited role in warm-antibody AIHA (w-AIHA), whereas primary cold agglutinin disease (CAD), secondary cold agglutinin syndrome (CAS), and paroxysmal cold hemoglobinuria (PCH) are entirely complement-dependent disorders. [ 5 ]


Hemolysis induced by cold agglutinin disease taking place  outside  the vessels while which of Donath–Landsteiner antibodies is taking place  inside  the vessels. [ 10 ] [ 9 ]


Complement component 4  ( C4 ), in humans, is a protein involved in the intricate  complement system , originating from the  human leukocyte antigen  (HLA) system. It serves a number of critical functions in immunity, tolerance, and autoimmunity with the other numerous components. Furthermore, it is a crucial factor in connecting the recognition pathways of the overall system instigated by antibody-antigen (Ab-Ag) complexes to the other effector proteins of the innate immune response. For example, the severity of a dysfunctional  complement system  can lead to fatal diseases and infections. Complex variations of it can also lead to  schizophrenia . [ 1 ]  The C4 protein was thought to derive from a simple two-locus allelic model, which however has been replaced by a much more sophisticated multimodular  RCCX  gene complex model which contain long and short forms of the  C4A  or  C4B  genes usually in tandem  RCCX  cassettes with copy number variation, that somewhat parallels variation in the levels of their respective proteins within a population along with  CYP21  in some cases depending on the number of cassettes and whether it contains the functional gene instead of pseudogenes or fragments. [ 2 ]  Originally defined in the context of the Chido/Rodgers blood group system, the C4A-C4B genetic model is under investigation for its possible role in  schizophrenia  risk and development.


One of the earlier genetic studies on the C4 protein identified two different groups, found within a human serum, called the Chido/Rogers (Ch/Rg) blood groups. O’Neill et al. have demonstrated that two different C4 loci express the different Ch/Rg antigens on the membranes of erythrocytes. [ 3 ]  More specifically, the two proteins, Ch and Rg, function together as a medium for interaction between the Ab-Ag complex and other complement components. [ 4 ]  Moreover, the two loci are linked to the HLA, or the human analog of the  major histocompatibility complex  (MHC) on the short arm of chromosome 6, whereas previously they were believed to have been expressed by two codominant alleles at a single locus. [ 3 ] [ 5 ]  In gel electrophoresis studies, O’Neill et al. have identified two genetic variants: F, signifying the presence (F+) or absence (f0/ f0) of four fast moving bands, and S, signifying the presence (S+) or absence (s0/ s0) of four slow moving bands. [ 3 ]  The homogeneity or heterogeneity of the two loci, with the addition of these null (f0, s0) genes, allow for duplication/non-duplication of the C4 loci. [ 6 ]  Therefore, having separate loci for C4, C4F and C4S (later identified as C4A or C4B, respectively), possibly account for producing multiple allelic forms, leading to the great size and  copy number variation . [ citation needed ]


Two important contributors, Carroll and Porter, in their study of cloning the human C4 gene showed that all six of their clones contained the same C4 gene. [ 7 ]  The C4 protein consists of 3 subunits (α, β, and γ) having molecular weights (MWs) of ~95,000, 78,000, and 31,000, respectively and they are all joined by interchain disulfide bridges. [ 7 ] [ 8 ] [ 9 ] [ 10 ]  In a study by Roos et al., the α-chains between the C4A and C4B were found to be slightly different (MW of ~96,000 and 94,000, respectively), proving that there is actually a structural difference between the two variants. [ 9 ]  Moreover, they implicated that a lack of C4 activity could be attributed to the structural differences between the α-chains. [ 9 ]  Nevertheless, Carroll and Porter demonstrated that there is a 1,500-bp region that acts as an  intron  in the genomic sequence, which they believed to be the known C4d region, a byproduct of C4 activity. [ 7 ]  Carroll et al. later published work that characterized the structure and organization of the C4 genes, which are situated in the HLA class III region and linked with C2 and factor B on the chromosome. [ 11 ]  Through experiments involving restriction mapping, nucleotide sequence analysis, and hybridization with C4A and C4B, they found that the genes are actually fairly similar though they have their differences. [ 11 ]  For example, single nucleotide polymorphisms were detected, which allowed them to be class differences between C4A and C4B. [ 11 ]  Furthermore, class and allelic differences would affect the performance of the C4 proteins with the immune complex. [ 11 ]  Finally, by overlapping cDNA cloned fragments, they were able to determine that the C4 loci, an estimated 16 kilobase (kb) long, are spaced by 10 kb and aligned 30 kb from the factor B locus. [ 10 ] [ 11 ]


In the same year, studies relatedly identified a 98 kb region of the chromosome the four class III genes (that express C4A, C4B, C2, and factor B) are closely linked, which does not allow for cross-overs to occur. [ 10 ]  Using protein variants visualized by electrophoresis, the four structural genes were located between HLA-B and HLA-D. [ 10 ]  More specifically, they verified the proposed molecular map in which the gene order went from  factor B , C4B, C4A, and C2 with C2 nearest to HLA-B. [ 10 ]  In another study, Law et al. then continued to delve deeper, this time comparing the properties of both the C4A and C4B, both of which are substantial players in the human immunity system. [ 12 ]  Through methods that include incubation, different pH levels, and treatment with methylamine, they had biochemically illustrated the different reactivities of the C4 genes. [ 12 ]  More specifically, the C4B has shown to react much more efficiently and effectively despite the 7 kb difference between C4A and C4B. In whole serum, C4B alleles performed at a rate several fold greater during hemolytic activity, in direct comparison with C4A alleles. [ 12 ]  Biochemically, they also found that C4A reacted more steadily with an antibody’s amino acid side chains and antigens that are amino groups, while C4B reacted better with carbohydrate hydroxyl groups. [ 12 ]  Thus, upon analysis of the varying reactivities, they proposed that the exceptional polymorphism of C4 genes may bring about some biological advantages (i.e. complement activation with a more extensive range of Ab-Ag complexes formed upon infections). [ 12 ]  Though at this point in time, the genomic and derived amino acid sequence of either C4A or C4B had yet to be determined. [ citation needed ]


The early studies vastly expanded the knowledge of the C4 complex, laying down the foundations that paved the way to discovering the gene and protein structures. C. Yu successfully determined the complete sequence of the human complement component C4A gene. [ 4 ]  In the findings, the whole genome was found to have of 41 exons, with a total of 1744 residues (despite avoiding the sequence of a large Intron 9). [ 4 ]  The C4 protein is synthesized into a single chain precursor, which then undergoes proteolytic cleavage into three chains (in order of how they are chained, β-α-γ). [ 4 ]


The β-chain consists of 656 residues, coded by exons 1-16. [ 4 ]  The most prominent aspect of the β-chain is the presence of a large intron, ranging from six to seven kilobases in size. [ 4 ]  It is present in the first locus (coding for C4A) for all C4 genes and in the second locus (coding for C4B) only in a few C4 genes. [ 4 ]  The α-chain consists of residues 661-1428, encoding exons 16-33. [ 4 ]  Within this chain, two cleavage sites marked by exons 23 and 30 produces the C4d fragment (where the thioester, Ch/Rg antigens, and isotypic residues are located); moreover, most of the polymorphic sites cluster in this region. [ 4 ]  The γ-chain consists of 291 residues, encoding exons 33-41. [ 4 ]  Unfortunately, no specific function has been attributed to the γ-chain. [ 4 ]


The study completed by Vaishnaw et al. sought to identify the key region and factors related to the efforts of gene expression of the C4 gene. [ 13 ]  Their research concluded with the fact that the Sp1 binding site (positioned at -59 to -49) plays an important role in accurately starting basal transcription of C4. [ 13 ]  Utilization of electromobility shift assays and DNase I footprint analyses demonstrated specific DNA-protein correlations of the C4 promoter at the nuclear factor 1, two E box (-98 to -93 and -78 to -73), and Sp1 binding domains. [ 13 ]  These findings were later added to in another extensive study, that found a third E box site. [ 14 ]  In addition, the same findings postulated that two physical entities within the gene sequence could have a role in the expression levels of human C4A and C4B, which include the both presence of the endogenous retrovirus that can have positive or negative regulatory influences affecting C4 transcription and the varying genetic environment (dependent on which genetic modular component is present) past position -1524. [ 14 ]


To provide more context, in the latter study, the previously noted bimodular structure (C4A-C4B) has been updated to a quadrimodular structure of one to four discrete segments, containing one or more RP-C4-CYP21-TNX ( RCCX ) modules. [ 2 ]  The size of either C4A or C4B gene can be 21 kb (long, L) or 14.6 kb (short, S). Also, the long C4 gene uniquely contains a retrovirus HERV-K(C4) in its intron 9 that imposes  transcription  of an extra 6.36 kb, hence the “longer” string of gene. [ 2 ] [ 14 ]  Thus, C4 genes have a complex pattern of variation in gene size, copy number, and polymorphisms. [ 2 ] [ 14 ]  Examples of these mono-, bi-, tri-, and quadri-modular structures include: L or S (monomodular with one long or short C4 gene), LL or LS or SS (bimodular with a combination of homozygous or heterozygous L or S genes), LLL or LLS or LSS (trimodular RCCX with three L or S C4 genes), LLLL (quadrimodular structure with four L or S C4 genes). [ 14 ]  Not all the structural groups have the same percentage of appearance, possibly even further differences within separate ethnic groups. For example, the Caucasian population studied showed 69% bimodular configuration (C4A-C4B, C4A-C4A, or C4B-C4B) and 31% trimodular configuration (equally split between LLL as C4A-C4A-C4B or LSS as C4A-C4B-C4B). [ 14 ]  Regarding C4 protein sequence polymorphism, a total of 24 polymorphic residues were found. Among them, the β-chain expressed of five, as the α-chain and γ-chain produced 18 and one, respectively. These polymorphisms can be further categorized into groups: 1) four isotypic residues at specific positions, 2) Ch/Rg antigenic determinants at specific positions, 3) C5 binding sites, 4) private allelic residues. [ 14 ]


Additionally, the same study identified the expression of human complement C4 transcripts in multiple tissues. The results of a Northern blot analysis, using a C4d probe and RD probe as positive control, showed that the liver contains the majority of transcripts throughout the body. [ 14 ]  Even so, moderate quantities were expressed in adrenal cortices/medulla, thyroid, and kidney. [ 14 ]


As noted, C4 (mixture of C4A and C4B) participates in all three of the complement pathways (classical, alternative, and lectin); the alternative pathway is "triggered spontaneously," while the classical and lectin pathways are elicited in response to the recognition of particular microbes. [ 16 ]  All three pathways converge at a step in which complement protein C3 is cleaved into proteins C3a and C3b, which results in a  lytic pathway  and formation of a  macromolecular assembly  of multiple proteins, termed the membrane-attack complex (MAC), which serves as a pore in the membrane of the targeted pathogen, leading to invading cell disruption and eventual lysis. [ 16 ]


In the  classical pathway,  the complement component—hereafter abbreviated by the "C" preceding the protein number— termed  C1s,  a  serine protease , is activated by upstream steps of the pathway, resulting in its cleavage of the native, parent ~200  kilodalton  (kDa) C4 protein—composed of three chains. [ 16 ] : 288   The C4 is cleaved by the protease into two parts, a peptide C4a (small at ~9 kDa, and  anaphylotoxic ), and the higher molecular weight protein C4b, at about 190 kDa. [ 17 ]  The cleavage of the C4 results in C4b bearing a  thioester  functional group [-S-C(O)-]: work in the 1980s on C3, and then on C4, indicated the presence, within the parent C3 and C4 structures, of a unique protein modification, a 15-atom (15-membered)  thionolactone  ring serving to connect the thiol side chain of the amino acid cysteine (Cys) in a -Cys-Gly-Glu-Glx- sequence with a side chain  acyl group  of what began as a  glutamine  side chain (Glx, here) that resided three amino acid residues downstream (where the remaining atoms of the 15 were  backbone  and side chain atoms); [ 17 ] [ 18 ]  upon cleavage, this unique  thionolactone  ring structure becomes exposed at the surface of the new C4b protein. [ 16 ] [ 17 ] [ 18 ]  Because of proximity to the microbial surface, some portion of the released C4b proteins, with this reactive thionolactone, react with  nucleophilic  amino acid side chains and other groups on the foreign microbe's cell surface, resulting in  covalent  attachment of the slightly modified C4b protein to the cell surface, via the original Glx residue of C4. [ 16 ] [ 17 ] [ 18 ]


C4b has further functions. It interacts with protein C2; the same protease invoked earlier, C1s, then cleaves C2 into two parts, termed C2a and C2b, with C2b being released, and C2a remaining in association with C4b; the C4b-C2a complex of the two proteins then exhibits a further system-associated protease activity toward protein C3 (cleaving it), with subsequent release of both proteins, C4b and C2a, from their complex (whereupon C4b can bind another protein C2, and conduct these steps again). [ 16 ]  Because C4b is regenerated, and a cycle is created, the C4b-C2a complex with protease activity has been termed the  C3 convertase. [ 16 ]  Protein 4b can be further cleaved into 4c and 4d. [ 19 ]


Although other diseases (i.e.  systemic lupus erythematosus ) have been implicated, the C4 gene is also being investigated for the role it may play in schizophrenia risk and development. In the Wu et al. study, they utilized the real-time polymerase chain reaction (rt-PCR) as an assay to determine the copy number variance (CNV) or genetic diversity of C4. [ 20 ]  Accordingly, with these results, future prognoses, flares, and remissions will become more feasible to determine. The results basically show copy number variants as a mechanism to effect genetic diversity. As discussed before, the different phenotypes allowed for by the varying genetic variety of complement C4 include a wide range of plasma or serum C4 proteins among two isotypes—C4A and C4B—with multiple protein allotypes that can have unique physiological functions. [ 20 ]  CNVs are sources of inherent genetic diversity and are engaged in gene-environment interaction. [ 20 ]  CNVs (and associated polymorphisms) play a role in filling in the gap towards understanding the genetic basis of quantitative traits and the different susceptibilities to autoimmune and neurobiological diseases. [ citation needed ]


Substantial data from all over the world has been collected and analyzed to determine that schizophrenia, indeed, has a strong genetic relationship with a region in the MHC locus on chromosome arm 6. [ 21 ] [ 1 ]


Data and information collected internationally can shed light onto the mysteries of  schizophrenia . Sekar et al. analyzed  single nucleotide polymorphisms  (SNP) of 40 cohorts in 22 countries, in total adding up to nearly 29,000 cases. [ 1 ]  They found out two features: 1) A great number of SNPs reaching only 2Mb across the end, 2) peak of association centered at C4, predicting that C4A expression levels is most strongly correlated with schizophrenia. [ 1 ]  In addition, they have discovered a mechanism by which schizophrenia could arise from the genetic predisposition of the human complement C4. [ 1 ]  As shown in Figure 1, four common  structural variations  discovered in  genome-wide association studies  (GWAS) studies have pointed to the high turnout of schizophrenia. [ 1 ]  Possibly, the higher levels of expression of C4 protein due to pattern of variants of the C4 gene, allows for the unwanted increase in  synaptic pruning  (an effect produced by the effector proteins of the  complement system  in which the C4 partakes).


Congenital rubella syndrome  (CRS) occurs when a human  fetus  is infected with the  rubella virus  (German measles) via maternal-fetal transmission and develops  birth defects . [ 1 ]  The most common congenital defects affect the ophthalmologic, cardiac, auditory, and neurologic systems. [ 2 ]


Rubella infection in pregnancy can result in various outcomes ranging from asymptomatic infection to  congenital defects  to  miscarriage  and fetal death. [ 3 ] [ 4 ]  If infection occurs 0–11 weeks after conception, the infant has a 90% risk of being affected. [ 1 ]  If the infection occurs 12–20 weeks after conception, the risk is 20%. Infants are not generally affected if rubella is contracted during the third trimester. [ 3 ]  Diagnosis of congenital rubella syndrome is made through a series of clinical and laboratory findings and management is based on the infant's clinical presentation. Maintaining  rubella  outbreak control via vaccination is essential in preventing congenital rubella infection and congenital rubella syndrome. [ 3 ]


Congenital rubella syndrome was discovered in 1941 by Australian  Norman McAlister Gregg . [ 5 ]


The classic triad for congenital rubella syndrome is: [ 8 ]


Other manifestations of CRS may include:


Children who have been exposed to rubella in the womb should also be watched closely as they age for any indication of:


Diagnosis of congenital rubella syndrome is made based on clinical findings and laboratory criteria. [ 3 ]  Laboratory criteria includes at least one of the following:


Clinical definition is characterized by findings in the following categories:


A patient is classified into the following cases depending on their clinical and laboratory findings: [ 3 ]


Vaccinating the majority of the population is effective at preventing congenital rubella syndrome. [ 25 ]  With the introduction of the rubella vaccine in 1969, the number of cases of rubella in the United States has decreased 99%, from 57,686 cases in 1969 to 271 cases in 1999. [ 3 ]  For women who plan to become pregnant, the  MMR (measles mumps, rubella) vaccination  is highly recommended, at least 28 days prior to conception. [ 17 ]  The vaccine should not be given to women who are already pregnant as it contains live viral particles. [ 17 ]  Other preventative actions can include the screening and vaccinations of high-risk personnel, such as medical and child care professions. [ 26 ]


Infants with birth defects suspected to be caused by congenital rubella infection should be investigated thoroughly. Confirmed cases should be reported to the local or state health department to assess control of the virus and isolation of the infant should be maintained. [ 27 ]


Infants with known rubella exposure during pregnancy or those with a confirmed or suspected infection should receive close follow-up and supportive care. There are no medications or antivirals that will shorten the clinical course of the virus. [ 4 ]  Only those with  immunity  to rubella should have contact with infected infants, as they can shed viral particles in their respiratory secretions though 1 year of age (unless they test with repeated negative viral cultures at age 3 months). [ 3 ]  Many infants can be born with multiple birth defects that require multidisciplinary management and interventions based on clinical manifestations. Often these infants will require extended period or life-long follow up with medical specialists. Early diagnosis of congenital rubella syndrome is important for planning future medical care and educational placement. [ 19 ]


Many infants with CRS may be born with  sensorineural deafness  and thus should undergo a newborn hearing evaluation. Hearing loss may not be apparent at birth and thus requires close auditory follow up. Infants with confirmed hearing impairment may require hearing aids and may benefit from an early intervention program. [ 4 ]


Eye abnormalities including cataracts, infantile glaucoma and retinopathy are common in infants born with CRS. [ 27 ]  Infants should undergo eye examinations after birth and during early childhood. Those with congenital eye defects require care from a pediatric ophthalmologist for specialized care and follow up. [ 4 ]


Congenital cardiac anomalies including  pulmonary artery stenosis  and  patent ductus arteriosus  can be seen in infants with CRS. Infants should undergo cardiac evaluation soon after birth and those with confirmed cardiac lesions will require specialized care with a pediatric cardiologist for any interventions and follow-up care. [ 4 ]


Critical green inclusions , also known as  green neutrophilic inclusions  and informally,  death crystals  or  crystals of death , [ 1 ] [ 2 ]  are amorphous blue-green  cytoplasmic inclusions  found in  neutrophils  and occasionally in  monocytes . They appear brightly coloured and refractile when stained with  Wright-Giemsa stain . These inclusions are most commonly found in critically ill patients, particularly those with  liver disease , and their presence on the  peripheral blood smear  is associated with a high short-term mortality rate. [ 3 ] [ 4 ]


Critical green inclusions are a rare finding, and when found they are suggestive of a poor prognosis, hence the colloquial term  death crystals . A 2018 review found that 56% of patients died shortly after the inclusions were first identified (usually within two weeks). [ 5 ]  However, critical green inclusions are of limited utility for predicting mortality because they are usually found in severely ill patients whose poor prognosis is already evident for other reasons by the time the crystals are detected. [ 6 ]


The inclusions were once hypothesized to be bile products  phagocytized  during fulminant hepatic injury, due to the high incidence of critical green inclusions observed in cases of acute hypoxic and ischaemic  hepatitis . [ 7 ]  However, recent studies have highlighted that the inclusions stain positive for  Oil Red O  as opposed to bile stains, suggesting high lipid content. [ 8 ]  Additionally, some cases with critical green inclusions were not associated with notable hepatic injury. Currently, it is suggested that critical green inclusions are more likely to be phagocytized products of lysosomal degradation related to tissue injury. [ 8 ]


The composition of the inclusions is not well understood, but  transmission electron microscopy  has shown that they are rich in lipids and possibly related to  lipofuscin . Microscopic examination of liver tissue in patients with critical green inclusions has demonstrated prominent deposition of lipofuscin, suggesting that the white blood cell inclusions represent  phagocytosis  of this substance following severe injury to the liver. [ 3 ] [ 9 ]


Crizanlizumab , sold under the brand name  Adakveo  among others, is a  monoclonal antibody  medication that binds to  P-selectin . [ 3 ]  It is a medication used to reduce the frequency of  vaso-occlusive crisis  in people aged 16 years and older who have  sickle cell anemia . [ 3 ] [ 4 ] [ 6 ]  It is given by injection into a vein. [ 3 ] [ 4 ]


The most common side effects include joint pain, nausea, back pain, fever and abdominal (belly) pain. [ 4 ]


Crizanlizumab was approved for medical use in the United States in November 2019. [ 6 ] [ 7 ] [ 8 ]  The EU's EMA withdrew authorization in May 2023 based on no significant effects from a phase 3 trial. [ 9 ]  The U.S.  Food and Drug Administration  (FDA) considers it to be a  first-in-class medication . [ 10 ]


Crizanlizumab is  indicated  for the prevention of recurrent vaso occlusive crises in sickle cell disease patients aged 16 years and older. [ 4 ]  It can be given as an add on therapy to hydroxyurea/hydroxycarbamide (HU/HC) or as monotherapy in patients for whom HU/HC is inappropriate or inadequate. [ 3 ] [ 4 ]


Vaso-occlusive crisis is a common and painful complication of sickle cell disease that occurs when blood circulation is obstructed by sickled red blood cells (red cells are usually round and flexible, but sometimes many red cells in a person with sickle cell anemia will become rigid and crescent-shaped due to  polymerization  of hemoglobin). [ 11 ]


P-selectin  molecules are present on the surface of activated platelets and vascular  endothelial cells  and have been linked to sickle cell vaso-occlusive crises. [ 12 ] [ 13 ] [ 14 ]


The US  Food and Drug Administration  (FDA) approved crizanlizumab based on evidence from one clinical trial (Trial 1/NCT01895361) of 132 participants with sickle cell diseases who had a history of vaso-occlusive crisis. [ 8 ]  The trial was conducted at 60 sites in the United States, Brazil and Jamaica. [ 8 ]


The FDA granted the application for crizanlizumab  priority review ,  breakthrough therapy  designation, and  orphan drug  designation. [ 6 ]  The FDA granted approval of Adakveo to  Novartis . [ 6 ] [ 8 ]


The European Medicines Agency's human medicines committee (CHMP) has recommended the withdrawal of Adakveo (crizanlizumab), a medicine for preventing vaso-occlusive crises in patients with sickle cell disease, due to the lack of sufficient benefits outweighing the risks. [ 15 ]  The STAND phase III study showed that Adakveo does not effectively reduce the number of painful crises requiring healthcare visits or treatment at home compared to a placebo, and it exhibits a higher rate of severe side effects. [ 16 ] [ 17 ]


Immune activation :  Dostarlimab
 Other:   Ibalizumab


This  drug  article relating to the  blood  and  blood forming organs  is a  stub . You can help Wikipedia by  expanding it .


Cross-matching  or  crossmatching  is a test performed before a  blood transfusion  as part of  blood compatibility testing . Normally, this involves adding the recipient's  blood plasma  to a sample of the donor's  red blood cells . If the blood is incompatible, the  antibodies  in the recipient's plasma will bind to  antigens  on the donor red blood cells. This  antibody-antigen reaction  can be detected through visible  clumping  or  destruction  of the red blood cells, or by reaction with  anti-human globulin . Along with  blood typing  of the donor and recipient and  screening for unexpected blood group antibodies , cross-matching is one of a series of steps in pre-transfusion testing. In some circumstances, an  electronic cross-match  can be performed by comparing records of the recipient's  ABO  and  Rh blood type  against that of the donor sample. [ 1 ] : 600−3   In emergencies, blood may be issued before cross-matching is complete. [ 2 ] : 263   Cross-matching is also used to determine compatibility between a donor and recipient in solid  organ transplantation  including heart/lung transplation. [ 3 ] [ 4 ]


Immediate-spin cross-matching (ISCM) is an abbreviated form of cross-matching that is faster, but less  sensitive ; its primary use is to detect a mismatch between ABO blood types. It is an immediate test that involves combining the patient's serum and donor's red blood cells at room temperature, then  centrifuging  the sample and observing for agglutination or hemolysis. A lack of agglutination or hemolysis indicates a negative test reaction, or compatible match. [ 1 ] : 603   ISCM is not appropriate in all circumstances; if the recipient's antibody screen is positive, or if they have had a positive antibody screen in the past, a full crossmatch is performed instead. [ 2 ] : 261


The AHG crossmatch is done by incubating the recipient serum/plasma with the donor's red blood cells and adding anti-human globulin. It is essentially an indirect  Coomb's test . It is also called "full cross-matching", "IAT cross-matching" and "Coomb's cross-matching". [ 5 ]


Electronic cross-matching is a computer-assisted analysis using data, from the  donor  unit (where a donor's blood is tested prior to donation) and testing done on blood samples from the intended recipient. This includes  ABO / Rh  typing of the unit and of the recipient, and an antibody screen of the recipient. Electronic cross-matching can only be used if a patient has a negative antibody screen, which means that they do not have any active  red blood cell  atypical  antibodies , or they are below the detectable level of current testing methods. If all of the data entered is compatible, the computer will print a compatibility label stating that the unit is safe to transfuse.


As the complete cross-matching process takes approximately 1 hour, it is not always used in emergencies.


In the case of an emergency, a type-specific blood to which the recipient has no antibodies, can be requested. It is thought that this lifesaving measure is of more benefit than any risk of an antibody-mediated  transfusion reaction . This type of blood has less risk of a serious transfusion reaction because it is both ABO compatible and Rhesus (Rh)-compatible.


Universal donor blood, which is both type O and Rh negative, can be given if the recipient's blood group is not known, as may happen in an emergency. It is the policy of some institutions to reserve the releasing of O− blood only for female patients of childbearing age. This serves two purposes. First, it preserves the lower stock of O− blood and secondly, this eliminates the risk of O− negative mothers forming anti-D (Rh) antibodies from exposure to O+ blood. Anti-D (Rh) can cross the placenta during pregnancy and attack an unborn child's RBCs if they are D (Rh) positive causing  haemolytic disease of the newborn .


In an emergency, blood grouping can be done easily and quickly in 2 or 3 minutes in the laboratory on glass slides with appropriate reagents, by trained technical staff. This method depends on the presence or absence of  agglutination  (clumping of red blood cells), which can usually be visualized directly. Presence of agglutination indicates incompatibility. Occasionally a light  microscope  may be needed. If laboratory services are not available, the bedside card method of blood grouping may be used, where a drop of the intended recipients blood is added to dried reagents on a prepared card. This method may not be as reliable as laboratory methods, which are preferable.


Dabie bandavirus , also called  SFTS virus , is a  tick-borne  virus in the genus  Bandavirus  in the family  Phenuiviridae , order  Bunyavirales . [ 2 ]  The clinical condition it caused is known as  severe fever with thrombocytopenia syndrome  (SFTS). [ 2 ]  SFTS is an emerging infectious disease that was first described in northeast and central China 2009 and now has also been discovered in Japan, South Korea, Vietnam and Taiwan in 2015. SFTS has a fatality rate of 12% and as high as over 30% in some areas. The major clinical symptoms of SFTS are fever, vomiting, diarrhea, multiple organ failure, thrombocytopenia (low platelet count), leukopenia (low white blood cell count) and elevated liver enzyme levels. Another outbreak occurred in East China in the early half of 2020.


In 2009, Xue-jie Yu and colleagues isolated the SFTS virus (SFTSV) from SFTS patients’ blood. [ 2 ]


The sequence of the genome was published in 2011. [ 2 ]  There are three segments—large (L), medium (M) and small (S). Five proteins have been identified—an  RNA dependent RNA polymerase  (RdRp), a glycoprotein N (Gn), a glycoprotein C (Gc), a nuclear protein (NP) and a non structural protein (NSs). [ 2 ]


The L segment encodes the RNA polymerase with 2084 amino acid residues. [ 2 ]


The M segment encodes one  open reading frame  encoding 1073 amino acid precursors of glycoproteins (Gn and Gc). [ 2 ]


The S segment has 1746 nucleotides of ambisense RNA encoding two proteins, the N and NSs proteins. These lie in opposite orientations and are separated by a 54 nucleotide intergenic region. [ 3 ]


The virus originated 50–150 years ago and has undergone a recent population expansion. [ 4 ]
Five genotypes (A–E) have been identified. [ 5 ]  Strains from  China  could be grouped into all five genotypes while isolates from  South Korea  lay in three (types A, D and E) and those from  Japan  only in one (type E). The virus appears to have originated in the  Dabie Mountains  in central China between 1918 and 1995. [ citation needed ]


Among bunyaviruses, it appears to be more closely related to the  Uukuniemi virus  serogroup than to the Sandfly fever group. [ 2 ]  It is a member of the Bhanja virus serocomplex. [ 6 ]


SFTSV is a tick-borne virus; it is not clear whether it can be transmitted by other blood-sucking arthropods. [ 7 ]  It can infect many mammalian hosts, including  cats ,  mice ,  hedgehogs ,  weasels ,  brushtail possums  and  yaks . Humans appear to be accidental hosts, and play no essential role in the life cycle of SFTSV. SFTSV has been detected from the ixodid  tick ,  Haemaphysalis longicornis ,  Ixodes nipponensis ,  Amblyomma testudinarium [ 8 ]  and  Rhipicephalus microplus . [ 9 ]  In addition to tick bite, SFTSV can be transmitted from person to person through contact with blood or mucus of an infected person. [ 10 ] [ 11 ]


This virus has been found in the Chinese provinces of  Anhui ,  Henan ,  Hubei ,  Jiangsu ,  Liaoning  and  Shandong . SFTS occurs in rural areas, from March to November, and a majority of cases are found from April to July. [ citation needed ]


The virus has also been found in South Korea, Japan, Vietnam and Taiwan. [ 12 ] [ 13 ] [ 14 ]


Danicopan , sold under the brand name  Voydeya , is a medication used for the treatment of  paroxysmal nocturnal hemoglobinuria . [ 6 ] [ 7 ]  It is a  complement  inhibitor which reversibly binds to factor D to prevent alternative pathway-mediated  hemolysis  and deposition of  complement C3  proteins on red blood cells. [ 7 ]


The most common side effects include fever, headache, increased levels of liver enzymes (a sign of possible liver problems) and pain in the extremities (arms and legs). [ 7 ]


Danicopan was approved for medical use in Japan in January 2024, [ 9 ]  in the United States in March 2024, [ 6 ] [ 10 ]  and in the European Union in April 2024. [ 7 ]


Danicopan is  indicated  as add-on therapy to  ravulizumab  or  eculizumab  for the treatment of extravascular hemolysis in adults with paroxysmal nocturnal hemoglobinuria. [ 6 ] [ 7 ]


Danicopan was approved for medical use in Japan, [ 11 ]  the United States, [ 6 ]  and the European Union in 2024. [ 7 ]  The FDA granted the application  breakthrough therapy  designation. [ 12 ]


In February 2024, the  Committee for Medicinal Products for Human Use  of the EMA adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Voydeya, intended as add-on therapy to ravulizumab or eculizumab for the treatment of residual hemolytic anemia in adults with paroxysmal nocturnal hemoglobinuria (PNH). [ 7 ] [ 13 ]  The applicant for this medicinal product is Alexion Europe. [ 7 ]  Danicopan was approved for medical use in the European Union in April 2024. [ 7 ] [ 8 ]


In October 2024, the  National Institute for Health and Care Excellence (NICE)  adopted a recommendation for danicopan as an add-on therapy for adults with the  paroxysmal nocturnal haemoglobinuria (PNH)  based results from the phase 3 ALPHA trial, which evaluated the efficacy and safety of the drug as an add-on to  ravulizumab  or  eculizumab  in patients with PNH who experienced clinically significant extravascular haemolysis. [ 14 ]


Danicopan is the  international nonproprietary name . [ 15 ]


This  pharmacology -related article is a  stub . You can help Wikipedia by  expanding it .


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NM_007827 NM_001317361


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NP_001304290 NP_031853 NP_001391877


Complement decay-accelerating factor , also known as  CD55  or  DAF , is a  protein  that, in humans, is encoded by the  CD55   gene . [ 5 ]


DAF regulates the  complement system  on the  cell  surface. It recognizes C4b and C3b fragments that are created during activation of C4 ( classical  or  lectin  pathway) or C3 ( alternative  pathway). Interaction of DAF with cell-associated C4b of the classical and lectin pathways interferes with the conversion of C2 to C2b, thereby preventing formation of the C4b2a  C3-convertase , and interaction of DAF with C3b of the alternative pathway interferes with the conversion of factor B to Bb by factor D, thereby preventing formation of the C3bBb C3 convertase of the alternative pathway. Thus, by limiting the amplification convertases of the complement
cascade, DAF indirectly blocks the formation of the  membrane attack complex . [ 6 ]


This  glycoprotein  is broadly distributed among  hematopoietic  and non-hematopoietic cells. It is a determinant for the Cromer blood group system.


DAF is a 70  kDa   membrane protein  that attaches to the cell membrane via a  glycophosphatidylinositol  (GPI) anchor.


DAF contains four  complement control protein  (CCP) repeats with a single N-linked glycan positioned between CCP1 and CCP2. CCP2, CCP3, CCP4 and three consecutive  lysine  residues in a positively charged pocket between CCP2 and CCP3 are involved in its inhibition of the  alternate complement pathway . CCP2 and CCP3 alone are involved in its inhibition of the  classical pathway . [ 7 ]


Because DAF is a  GPI -anchored protein, its expression is reduced in persons with mutations that reduce GPI levels such as those with  paroxysmal nocturnal hemoglobinuria  (PNH). In PNH disorder,  red blood cells  with very low levels of DAF and  CD59  undergo  complement -mediated hemolysis. Symptoms include low red blood cell count (anemia), fatigue, and episodes of dark colored urine and other complications. [ 8 ]


DAF is used as a receptor by some  coxsackieviruses  and other  enteroviruses . [ 9 ]  Recombinant soluble DAF- Fc  has been tested in mice as an anti-enterovirus therapy for heart damage; [ 10 ]  however, the human enterovirus that was tested binds much more strongly to human DAF than to  mouse  or  rat  DAF. Echoviruses and coxsackie B viruses that use human decay-accelerating factor (DAF) as a receptor do not bind the rodent analogues of DAF. [ 11 ]  and DAF-Fc has yet to be tested in humans.


Binding of DAF to human HIV-1 when the virons are budding from the surface of infected cells protects HIV-1 from complement mediated lysis. [ 12 ] [ 13 ]


Deep vein thrombosis  ( DVT ) is a type of  venous thrombosis  involving the formation of a  blood clot  in a  deep vein , most commonly in the legs or pelvis. [ 9 ] [ a ]  A minority of DVTs occur in the arms. [ 11 ]  Symptoms can include pain, swelling, redness, and enlarged veins in the affected area, but some DVTs have no symptoms. [ 1 ]


The most common life-threatening concern with DVT is the potential for a clot to  embolize  (detach from the veins), travel as an  embolus  through the right side of the heart, and become lodged in a  pulmonary artery  that supplies blood to the  lungs . This is called a  pulmonary embolism  (PE). DVT and PE comprise the  cardiovascular disease  of  venous thromboembolism  (VTE). [ 2 ]


About two-thirds of VTE manifests as DVT only, with one-third manifesting as PE with or without DVT. [ 12 ]  The most frequent long-term DVT  complication  is  post-thrombotic syndrome , which can cause pain, swelling, a sensation of heaviness, itching, and in severe cases,  ulcers . [ 5 ]  Recurrent VTE occurs in about 30% of those in the ten years following an initial VTE. [ 3 ]


The mechanism behind DVT formation typically involves some combination of  decreased blood flow , increased  tendency to clot , changes to the  blood vessel wall , and inflammation. [ 13 ]  Risk factors include recent surgery, older age, active  cancer ,  obesity , infection, inflammatory diseases,  antiphospholipid syndrome , personal history and  family history  of VTE, trauma, injuries, lack of movement,  hormonal birth control ,  pregnancy , and the  period following birth . VTE has a strong genetic component, accounting for approximately 50 to 60% of the variability in VTE rates. [ 4 ]  Genetic factors include non-O  blood type , deficiencies of  antithrombin ,  protein C , and  protein S  and the mutations of  factor V Leiden  and  prothrombin G20210A . In total, dozens of genetic risk factors have been identified. [ 4 ] [ 14 ]


People suspected of having DVT can be assessed using a  prediction rule  such as the  Wells score . A  D-dimer  test can also be used to assist with excluding the diagnosis or to signal a need for further testing. [ 5 ]  Diagnosis is most commonly confirmed by  ultrasound  of the suspected veins. [ 5 ]  VTE becomes much more common with age. The condition is rare in children, but occurs in almost 1% of those ≥ age 85 annually. [ 3 ]  Asian, Asian-American, Native American, and Hispanic individuals have a lower VTE risk than Whites or Blacks. [ 4 ] [ 15 ]  Populations in Asia have VTE rates at 15 to 20% of what is seen in Western countries. [ 16 ]


Using  blood thinners  is the standard treatment. Typical medications include  rivaroxaban ,  apixaban , and  warfarin . Beginning warfarin treatment requires an additional non-oral anticoagulant, often injections of  heparin . [ 17 ] [ 18 ] [ 19 ]


Prevention of VTE for the general population includes avoiding obesity and maintaining an active lifestyle. Preventive efforts following low-risk surgery include early and frequent walking. Riskier surgeries generally prevent VTE with a blood thinner or  aspirin  combined with  intermittent pneumatic compression . [ 7 ]


Symptoms classically affect a leg and typically develop over hours or days, [ 20 ]  though they can develop suddenly or over a matter of weeks. [ 21 ]  The legs are primarily affected, with 4–10% of DVT occurring in the arms. [ 11 ]  Despite the signs and symptoms being highly variable, [ 5 ]  the typical symptoms are pain,  swelling , and redness. However, these symptoms might not manifest in the lower limbs of those unable to walk. [ 22 ]  In those who are able to walk, DVT can reduce one's ability to do so. [ 23 ]  The pain can be described as throbbing and can worsen with weight-bearing, prompting one to bear more weight with the unaffected leg. [ 21 ] [ 24 ]


Additional signs and symptoms include tenderness,  pitting edema  ( see image ), dilation of surface veins, warmth, discoloration, a "pulling sensation", and even  cyanosis  (a blue or purplish discoloration) with fever. [ 5 ] [ 20 ] [ 21 ]  DVT can also exist without causing any symptoms. [ 22 ]  Signs and symptoms help in determining the likelihood of DVT, but they are not used alone for diagnosis. [ 19 ]


At times, DVT can cause symptoms in both arms or both legs, as with bilateral DVT. [ 25 ]  Rarely, a clot in the  inferior vena cava  can cause both legs to swell. [ 26 ]   Superficial vein thrombosis , also known as  superficial thrombophlebitis , is the formation of a  blood clot (thrombus)  in a  vein close to the skin . It can co-occur with DVT and can be felt as a "palpable cord". [ 20 ]   Migratory thrombophlebitis (Trousseau's syndrome)  is a noted finding in those with  pancreatic cancer  and is associated with DVT. [ 27 ]


A  pulmonary embolism  (PE) occurs when a blood clot from a  deep vein  (a DVT) detaches from a vein ( embolizes ), travels through the right side of the heart, and becomes lodged as an  embolus  in a  pulmonary artery  that supplies deoxygenated blood to the lungs for oxygenation. [ 28 ]  Up to one-fourth of PE cases are thought to result in sudden death. [ 12 ]  When not fatal, PE can cause symptoms such as sudden onset  shortness of breath  or  chest pain , coughing up blood ( hemoptysis ), and fainting ( syncope ). [ 29 ] [ 30 ]  The chest pain can be  pleuritic  (worsened by deep breaths) [ 29 ]  and can vary based upon where the embolus is lodged in the lungs. An estimated 30–50% of those with PE have detectable DVT by  compression ultrasound . [ 30 ]


A rare and massive DVT that causes significant obstruction and discoloration (including cyanosis) is  phlegmasia cerulea dolens . [ 31 ] [ 32 ]  It is life-threatening, limb-threatening, and carries a risk of venous  gangrene . [ 33 ]  Phlegmasia cerulea dolens can occur in the arm but more commonly affects the leg. [ 34 ] [ 35 ]  If found in the setting of acute  compartment syndrome , an urgent  fasciotomy  is warranted to protect the limb. [ 36 ]   Superior vena cava syndrome  is a rare complication of arm DVT. [ 11 ]


DVT is thought to be able to cause a  stroke  in the presence of a  heart defect . This is called a  paradoxical embolism  because the clot abnormally travels from the pulmonary circuit to the systemic circuit while inside the heart. The  defect  of a  patent foramen ovale  is thought to allow clots to travel through the  interatrial septum  from the  right atrium  into the left atrium. [ 37 ] [ 38 ]


In most suspected cases, DVT is ruled out after evaluation. [ 39 ]   Cellulitis  is a frequent mimic of DVT, with its  triad  of pain, swelling, and redness. [ 20 ]  Symptoms concerning for DVT are more often due to other causes, including cellulitis, ruptured  Baker's cyst ,  hematoma ,  lymphedema , and  chronic venous insufficiency . [ 1 ]  Other  differential diagnoses  include tumors, venous or arterial  aneurysms ,  connective tissue disorders , [ 40 ]   superficial vein thrombosis , muscle vein thrombosis, and  varicose veins . [ 41 ]


DVT and PE are the two manifestations of the  cardiovascular disease   venous thromboembolism  (VTE). [ 2 ]  VTE can occur as DVT only, DVT with PE, or PE only. [ 3 ]  About two-thirds of VTE manifests as DVT only, with one-third manifesting as PE with or without DVT. [ 12 ]  VTE, along with superficial vein thrombosis, are common types of venous thrombosis. [ 10 ]


DVT is classified as  acute  when the clots are developing or have recently developed, whereas  chronic  DVT persists more than 28 days. [ 42 ]  Differences between these two types of DVT can be seen with ultrasound. [ 43 ]  An episode of VTE after an initial one is classified as recurrent. [ 44 ] [ 45 ]  Bilateral DVT refers to clots in both limbs while unilateral means only a single limb is affected. [ 46 ]


DVT in a leg above the knee is termed  proximal DVT  ( proximal ). DVT in a leg below the knee is termed  distal DVT  ( distal ), also called  calf DVT  when affecting the calf, [ 47 ] [ 48 ]  and has limited  clinical significance  compared to proximal DVT. [ 49 ]  Calf DVT makes up about half of DVTs. [ 50 ]   Iliofemoral DVT  is described as involving either the  iliac , or  common femoral vein ; [ 51 ]  elsewhere, it has been defined as involving at a minimum the  common iliac vein , which is near the top of the pelvis. [ 19 ]


DVT can be classified into provoked and unprovoked categories. [ 52 ]  For example, DVT that occurs in association with cancer or surgery can be classified as provoked. [ 52 ]  However, the  European Society of Cardiology  in 2019 urged for this dichotomy to be abandoned to encourage more personalized risk assessments for recurrent VTE. [ 53 ]  The distinction between these categories is not always clear. [ 54 ]


Traditionally, the three factors of  Virchow's triad — venous stasis ,  hypercoagulability , and changes in the  endothelial  blood vessel lining—contribute to VTE and were used to explain its formation. [ 55 ]  More recently,  inflammation  has been identified as playing a clear causal role. [ 13 ]  Other related causes include activation of  immune system  components, the state of  microparticles  in the blood, the concentration of oxygen, and possible  platelet  activation. [ 56 ]  Various risk factors contribute to VTE, including genetic and environmental factors, though many with multiple risk factors never develop it. [ 57 ] [ 58 ]


Acquired risk factors include the strong risk factor of older age, [ 5 ]  which alters blood composition to favor clotting. [ 59 ]  Previous VTE, particularly unprovoked VTE, is a strong risk factor. [ 60 ]  A leftover clot from a prior DVT increases the risk of a subsequent DVT. [ 61 ]  Major surgery and  trauma  increase risk because of  tissue factor  from outside the vascular system entering the blood. [ 62 ]  Minor injuries, [ 63 ]  lower limb amputation, [ 64 ]   hip fracture , and  long bone  fractures are also risks. [ 9 ]  In  orthopedic surgery , venous stasis can be temporarily provoked by a cessation of blood flow as part of the procedure. [ 56 ]  Inactivity and immobilization contribute to venous stasis, as with  orthopedic casts , [ 65 ]  paralysis, sitting, long-haul travel, bed rest, hospitalization, [ 62 ]   catatonia , [ 66 ]  and in survivors of acute  stroke . [ 67 ]  Conditions that involve compromised blood flow in the veins are  May–Thurner syndrome , where a vein of the pelvis is compressed, and venous  thoracic outlet syndrome , which includes  Paget–Schroetter syndrome , where compression occurs near the base of the neck. [ 68 ] [ 69 ] [ 70 ]


Infections, including  sepsis ,  COVID-19 ,  HIV , and active  tuberculosis , increase risk. [ 71 ] [ 72 ] [ 73 ] [ 74 ] [ 75 ]  Chronic inflammatory diseases and some  autoimmune diseases , [ 76 ]  such as  inflammatory bowel disease , [ 77 ]   systemic sclerosis , [ 78 ]   Behçet's syndrome , [ 79 ]  primary  antiphospholipid syndrome , [ 80 ]  and  systemic lupus erythematosus  (SLE) [ 81 ]  increase risk. SLE itself is frequently associated with secondary antiphospholipid syndrome. [ 82 ]


Cancer can grow in and around veins, causing venous stasis, and can also stimulate increased levels of tissue factor. [ 83 ]  Cancers of the blood, lung, pancreas, brain, stomach, and bowel are associated with high VTE risk. [ 84 ]  Solid tumors such as  adenocarcinomas  can contribute to both VTE and  disseminated intravascular coagulation . In severe cases, this can lead to simultaneous clotting and bleeding. [ 85 ]   Chemotherapy  treatment also increases risk. [ 86 ]  Obesity increases the potential of blood to clot,  as does pregnancy.  In the  postpartum ,  placental  tearing releases substances that favor clotting. Oral contraceptives [ b ]  and  hormonal replacement therapy  increase the risk through a variety of mechanisms, including altered blood coagulation protein levels and reduced  fibrinolysis . [ 56 ]


Dozens of genetic risk factors have been identified, [ 14 ]  and they account for approximately 50 to 60% of the variability in VTE rates. [ 4 ]  As such,  family history  of VTE is a risk factor for a first VTE. [ 88 ]   Factor V Leiden , which makes  factor V  resistant to inactivation by  activated protein C , [ 88 ]  mildly increases VTE risk by about three times. [ 14 ] [ 88 ]  Deficiencies of three proteins that normally prevent blood from clotting— protein C ,  protein S , and  antithrombin —contribute to VTE. These  deficiencies in antithrombin ,  protein C , and  protein S [ c ]  are rare but strong, or moderately strong, risk factors. [ 62 ] [ 56 ]  They increase risk by about 10 times. [ 89 ]   Having a non-O blood type roughly doubles VTE risk. [ 56 ]  Non-O blood type is common globally, making it an important risk factor. [ 90 ]  Individuals without O blood type have higher blood levels of  von Willebrand factor  and  factor VIII  than those with O blood type, increasing the likelihood of clotting. [ 90 ]  Those  homozygous  for the common  fibrinogen gamma gene  variant rs2066865 have about a 1.6 times higher risk of VTE. [ 91 ]  The genetic variant  prothrombin G20210A , which increases prothrombin levels, [ 62 ]  increases risk by about 2.5 times. [ 14 ]  Additionally, approximately 5% of people have been identified with a background genetic risk comparable to the factor V Leiden and prothrombin G20210A mutations. [ 14 ]


Blood alterations including  dysfibrinogenemia , [ 65 ]  low free protein S, [ 58 ]   activated protein C resistance , [ 58 ]   homocystinuria , [ 92 ]   hyperhomocysteinemia , [ 62 ]   high  fibrinogen  levels, [ 62 ]  high  factor IX  levels, [ 62 ]  and high  factor XI  levels [ 62 ]  are associated with increased risk. Other associated conditions include  heparin-induced thrombocytopenia ,  catastrophic antiphospholipid syndrome , [ 93 ]   paroxysmal nocturnal hemoglobinuria , [ 94 ]   nephrotic syndrome , [ 58 ]   chronic kidney disease , [ 95 ]   polycythemia vera ,  essential thrombocythemia , [ 96 ]  intravenous drug use, [ 97 ]  and smoking. [ d ]


Some risk factors influence the location of DVT within the body. In isolated distal DVT, the profile of risk factors appears distinct from proximal DVT. Transient factors, such as surgery and immobilization, appear to dominate, whereas  thrombophilias [ e ]  and age do not seem to increase risk. [ 101 ]  Common risk factors for having an upper extremity DVT include having an existing foreign body (such as a central venous catheter, a pacemaker, or a triple-lumen PICC line), cancer, and recent surgery. [ 11 ]


Blood has a natural tendency to clot when blood vessels are damaged ( hemostasis ) to minimize blood loss. [ 102 ]  Clotting is activated by the  coagulation cascade  and the clearing of clots that are no longer needed is accomplished by the process of  fibrinolysis . Reductions in fibrinolysis or increases in coagulation can increase the risk of DVT. [ 102 ]


DVT often develops in the calf veins and "grows" in the direction of venous flow, towards the heart. [ 42 ] [ 103 ]  DVT most frequently affects veins in the leg or pelvis [ 9 ]  including the  popliteal vein  (behind the knee),  femoral vein  (of the thigh), and iliac veins of the pelvis. Extensive lower-extremity DVT can even reach into the  inferior vena cava  (in the abdomen). [ 104 ]  Upper extremity DVT most commonly affects the subclavian, axillary, and  jugular veins . [ 11 ]


The process of fibrinolysis, where DVT clots can be dissolved back into the blood, acts to temper the process of thrombus growth. [ 105 ]  This is the preferred process. Aside from the potentially deadly process of embolization, a clot can resolve through organization, which can damage the valves of veins, cause vein fibrosis, and result in non-compliant veins. [ 106 ] [ 107 ]  Organization of a thrombus into the vein can occur at the third stage of its  pathological  development, in which collagen becomes the characteristic component. The first pathological stage is marked by red blood cells, and the second is characterized by medium-textured fibrin. [ 107 ]


In arterial thrombosis, blood vessel wall damage is required, as it initiates  coagulation , [ 108 ]  but clotting in the veins mostly occurs without any such mechanical damage. [ 62 ]  The beginning of venous thrombosis is thought to arise from "activation of endothelial cells, platelets, and leukocytes, with initiation of inflammation and formation of microparticles that trigger the coagulation system" via tissue factor. [ 77 ]  Vein wall inflammation is likely the inciting event. [ 77 ]  Importantly, the  activated endothelium  of veins interacts with circulating white blood cells (leukocytes). [ 55 ]  While leukocytes normally help prevent blood from clotting (as does normal endothelium), upon stimulation, leukocytes facilitate clotting. [ 109 ]  Neutrophils are recruited early in the process of venous thrombi formation. [ 55 ]  They release pro-coagulant granules [ 109 ]  and  neutrophil extracellular traps  (NETs) or their components, which play a role in venous thrombi formation. [ 55 ] [ 110 ]  NET components are pro-thrombotic through both the intrinsic and extrinsic coagulation pathways. [ 110 ]  NETs provide "a scaffold for adhesion" of platelets, red blood cells, and multiple factors that potentiate platelet activation. [ 111 ]  In addition to the pro-coagulant activities of neutrophils, multiple stimuli cause  monocytes  to release tissue factor. [ 109 ]  Monocytes are also recruited early in the process. [ 55 ]


Tissue factor, via the tissue factor– factor VIIa  complex, [ 112 ]  activates the extrinsic pathway of coagulation and leads to conversion of prothrombin to thrombin, followed by fibrin deposition. [ 86 ]  Fresh venous clots are  red blood cell  and  fibrin  rich. [ 42 ]  Platelets and  white blood cells  are also components. Platelets are not as prominent in venous clots as they are in arterial ones, but they can play a role. [ 56 ]  In cancer, tissue factor is produced by cancer cells. [ 84 ]  Cancer also produces unique substances that stimulate  factor Xa , cytokines that promote  endothelial dysfunction , and  plasminogen activator inhibitor-1 , which inhibits the breakdown of clots (fibrinolysis). [ 84 ]


Often, DVT begins in the valves of veins. [ 105 ]  The blood flow pattern in the valves can cause low oxygen concentrations in the blood ( hypoxemia ) of a valve sinus. Hypoxemia, which is worsened by venous stasis, activates pathways—ones that include  hypoxia-inducible factor-1  and  early-growth-response protein 1 . Hypoxemia also results in the production of  reactive oxygen species , which can activate these pathways, as well as  nuclear factor-κB , which regulates hypoxia-inducible factor-1  transcription . [ 86 ]  Hypoxia-inducible factor-1 and early-growth-response protein 1 contribute to monocyte association with endothelial proteins, such as  P-selectin , prompting monocytes to release tissue factor-filled  microvesicles , which presumably begin clotting after binding to the endothelial surface. [ 86 ]


D-dimers  are a  fibrin degradation product , a natural byproduct of fibrinolysis that is typically found in the blood. An elevated level [ f ]  can result from  plasmin  dissolving a clot—or other conditions. [ 113 ]  Hospitalized patients often have elevated levels for multiple reasons. [ 39 ]   Anticoagulation , the standard treatment for DVT, prevents further clot growth and PE, but does not act directly on existing clots. [ 114 ]


A  clinical probability assessment  using the  Wells score  (see column in the table below) to determine if a potential DVT is "likely" or "unlikely" is typically the first step of the diagnostic process. The score is used in suspected first lower extremity DVT (without any PE symptoms) in primary care and outpatient settings, including the  emergency department . [ 1 ] [ 5 ]  The numerical result (possible score −2 to 9) is most commonly grouped into either "unlikely" or "likely" categories. [ 1 ] [ 5 ]  A Wells score of two or more means DVT is considered "likely" (about a 28% chance), while those with a lower score are considered "unlikely" to have DVT (about a 6% chance). [ 39 ]  In those unlikely to have DVT, a diagnosis is excluded by a negative D-dimer blood test. [ 1 ]  In people with likely DVT,  ultrasound  is the standard  imaging  used to confirm or exclude a diagnosis. [ 5 ]  Imaging is also needed for hospital inpatients with suspected DVT and those initially categorized as unlikely to have DVT but who have a positive D-dimer test. [ 1 ]


While the Wells score is the predominant and most studied clinical prediction rule for DVT, [ 39 ] [ 115 ]  it does have drawbacks. The Wells score requires a subjective assessment regarding the likelihood of an alternate diagnosis and performs less well in the elderly and those with a prior DVT. The  Dutch Primary Care Rule  has also been validated for use. It contains only objective criteria but requires obtaining a D-dimer value. [ 116 ]  With this prediction rule, three points or less means a person is at low risk for DVT. A result of four or more points indicates an ultrasound is needed. [ 116 ]  Instead of using a prediction rule, experienced physicians can make a DVT  pre-test probability  assessment using clinical assessment and gestalt, but prediction rules are more reliable. [ 1 ]


Compression  ultrasonography for suspected deep vein thrombosis  is the standard diagnostic method, and it is highly sensitive for detecting an initial DVT. [ 118 ]  A  compression ultrasound  is considered positive when the vein walls of normally compressible veins do not collapse under gentle pressure. [ 39 ]  Clot visualization is sometimes possible, but is not required. [ 119 ]  Three compression ultrasound scanning techniques can be used, with two of the three methods requiring a second ultrasound some days later to rule out the diagnosis. [ 118 ]  Whole-leg ultrasound is the option that does not require a repeat ultrasound, [ 118 ]  but proximal compression ultrasound is frequently used because distal DVT is only rarely clinically significant. [ 117 ]  Ultrasound methods including  duplex  and  color flow Doppler  can be used to further characterize the clot [ 117 ]  and Doppler ultrasound is especially helpful in the non-compressible iliac veins. [ 119 ]


CT scan venography , MRI venography, or a non-contrast MRI are also diagnostic possibilities. [ 120 ]  The  gold standard  for judging imaging methods is contrast  venography , which involves injecting a peripheral vein of the affected limb with a contrast agent and taking X-rays, to reveal whether the venous supply has been obstructed. Because of its cost, invasiveness, availability, and other limitations, this test is rarely performed. [ 39 ]


Treatment for DVT is warranted when the clots are either proximal, distal and symptomatic, or upper extremity and symptomatic. [ 2 ]  Providing anticoagulation, or blood-thinning medicine, is the typical treatment after patients are checked to make sure they are not subject to  bleeding . [ 2 ] [ i ]  However, treatment varies depending upon the location of DVT. For example, in cases of isolated distal DVT, ultrasound surveillance (a second ultrasound after 2 weeks to check for proximal clots), might be used instead of anticoagulation. [ 5 ] [ 124 ]  Although, those with isolated distal DVT at a high risk of VTE recurrence are typically anticoagulated as if they had proximal DVT. Those at a low risk for recurrence might receive a four- to six-week course of anticoagulation, lower doses, or no anticoagulation at all. [ 5 ]  In contrast, those with proximal DVT should receive at least 3 months of anticoagulation. [ 5 ]


Some anticoagulants can be taken by mouth, and these oral medicines include  warfarin  (a  vitamin K antagonist ),  rivaroxaban  (a  factor Xa inhibitor ),  apixaban  (a factor Xa inhibitor),  dabigatran  (a  direct thrombin inhibitor ), and  edoxaban  (a factor Xa inhibitor). [ 2 ]  Other anticoagulants cannot be taken by mouth. These  parenteral  (non-oral) medicines include  low-molecular-weight heparin ,  fondaparinux , and  unfractionated heparin . Some oral medicines are sufficient when taken alone, while others require the use of an additional parenteral blood thinner. Rivaroxaban and apixaban are the typical first-line medicines, and they are sufficient when taken orally. [ 19 ]  Rivaroxaban is taken once daily, and apixaban is taken twice daily. [ 5 ]   Warfarin, dabigatran, and edoxaban require the use of a parenteral anticoagulant to initiate oral anticoagulant therapy. [ 19 ] [ 125 ]   When warfarin is initiated for VTE treatment, a 5-day minimum of a parenteral anticoagulant [ j ]  together with warfarin is given, which is followed by warfarin-only therapy. [ 17 ] [ 18 ]  Warfarin is taken to maintain an  international normalized ratio  (INR) [ k ]  of 2.0–3.0, with 2.5 as the target. [ 128 ]  The benefit of taking warfarin declines as the duration of treatment extends, [ 129 ]  and the risk of bleeding increases with age. [ 130 ]  Periodic INR monitoring is not necessary when first-line direct oral anticoagulants are used. Overall, anticoagulation therapy is complex, and many circumstances can affect how these therapies are managed. [ 131 ]


The duration of anticoagulation therapy (whether it will last 4 to 6 weeks, [ 5 ]  6 to 12 weeks, 3 to 6 months, [ 19 ]  or indefinitely) is a key factor in clinical  decision making . [ 52 ]  When proximal DVT is provoked by surgery or trauma a 3-month course of anticoagulation is standard. [ 19 ]  When a first VTE is proximal DVT that is either unprovoked or associated with transient non-surgical risk factor, low-dose anticoagulation beyond 3 to 6 months might be used. [ 19 ]  In those with an annual risk of VTE in excess of 9%, as after an unprovoked episode, extended anticoagulation is a possibility. [ 132 ]  Those who finish warfarin treatment after idiopathic VTE with an elevated D-dimer level show an increased risk of recurrent VTE (about 9% vs about 4% for normal results), and this result might be used in clinical decision making. [ 133 ]  Thrombophilia test results rarely play a role in the length of treatment. [ 80 ]


Treatment for acute leg DVT is suggested to continue at home for uncomplicated DVT instead of hospitalization. Factors that favor hospitalization include severe symptoms or additional medical issues. [ 12 ]  Early walking is suggested over bedrest. [ 134 ]  Graduated compression stockings—which apply higher pressure at the ankles and a lower pressure around the knees [ 126 ]  can be trialed for symptomatic management of acute DVT symptoms, but they are not recommended for reducing the risk of  post-thrombotic syndrome , [ 125 ]  as the potential benefit of using them for this goal "may be uncertain". [ 5 ]  Nor are compression stockings likely to reduce VTE recurrence. [ 135 ]  They are, however, recommended in those with isolated distal DVT. [ 5 ]


If someone decides to stop anticoagulation after an unprovoked VTE instead of being on lifelong anticoagulation, aspirin can be used to reduce the risk of recurrence, [ 136 ]  but it is only about 33% as effective as anticoagulation in preventing recurrent VTE. [ 52 ]   Statins  have also been investigated for their potential to reduce recurrent VTE rates, with some studies suggesting effectiveness. [ 137 ]


An unprovoked VTE might signal the presence of an unknown cancer, as it is an underlying condition in up to 10% of unprovoked cases. [ 1 ]  A thorough clinical assessment is needed and should include a  physical examination , a review of  medical history , and universal  cancer screening  done in people of that age. [ 19 ] [ 138 ]  A review of prior imaging is considered worthwhile, as is "reviewing baseline blood test results including  full blood count ,  renal  and  hepatic function ,  PT  and  APTT ." [ 138 ]  It is not recommended practice to obtain  tumor markers  or a  CT of the abdomen and pelvis  in asymptomatic individuals. [ 1 ]   NICE  recommends that further investigations are unwarranted in those without relevant signs or symptoms. [ 138 ]


Thrombolysis  is the injection of an enzyme into the veins to dissolve blood clots, and while this treatment has been proven effective against the life-threatening emergency clots of stroke and heart attacks, randomized controlled trials [ 139 ] [ 140 ] [ 141 ]  have not established a net benefit in those with acute proximal DVT. [ 5 ] [ 142 ]  Drawbacks of  catheter-directed thrombolysis  (the preferred method of administering the clot-busting enzyme [ 5 ] ) include a risk of bleeding, complexity, [ l ]  and the cost of the procedure. [ 125 ]  Although, while anticoagulation is the preferred treatment for DVT, [ 125 ]  thrombolysis is a treatment option for those with the severe DVT form of phlegmasia cerula dorens ( bottom left image ) and in some younger patients with DVT affecting the iliac and common femoral veins. [ 12 ]  Of note, a variety of  contraindications to thrombolysis  exist. [ 125 ]  In 2020, NICE kept their 2012 recommendations that catheter-directed thrombolysis should be considered in those with iliofemoral DVT who have "symptoms lasting less than 14 days, good functional status, a life expectancy of 1 year or more, and a low risk of bleeding." [ 138 ]


A mechanical thrombectomy device can remove DVT clots, particularly in acute iliofemoral DVT (DVT of the major veins in the pelvis), but there is limited data on its efficacy. It is usually combined with thrombolysis, and sometimes temporary IVC filters are placed to protect against PE during the procedure. [ 143 ]  Catheter-directed thrombolysis with thrombectomy [ 141 ]  against iliofemoral DVT has been associated with a reduction in the severity of post-thrombotic syndrome at an estimated cost-effectiveness ratio of about $138,000 [ m ]  per gained  QALY . [ 144 ] [ 145 ]  Phlegmasia cerulea dolens might be treated with catheter-directed thrombolysis and/or thrombectomy. [ 19 ] [ 143 ]


In DVT in the arm, the first (topmost) rib can be surgically removed as part of the typical treatment when the DVT is due to  thoracic outlet syndrome  or  Paget–Schroetter syndrome . This treatment involves initial anticoagulation followed by thrombolysis of the  subclavian vein  and staged  first rib resection  to relieve the thoracic outlet compression and prevent recurrent DVT. [ 146 ]


The placement of an  inferior vena cava filter  (IVC filter) is possible when either the standard treatment for acute DVT, anticoagulation, is  absolutely contraindicated  (not possible), or if someone develops a PE despite being anticoagulated. [ 138 ]  However, a 2020 NICE review found "little good evidence" for their use. [ 138 ]  A 2018 study associated IVC filter placement with a 50% reduction in PE, a 70% increase in DVT, and an 18% increase in 30 day mortality when compared to no IVC placement. [ 1 ] [ 148 ]  Other studies including a systematic review and meta-analysis did not find a difference in mortality with IVC placement. [ 30 ]  If someone develops a PE despite being anticoagulated, care should be given to optimize anticoagulation treatment and address other related concerns before considering IVC filter placement. [ 138 ]


Patients with a history of DVT might be managed by  primary care ,  general internal medicine ,  hematology ,  cardiology ,  vascular surgery , or  vascular medicine . [ 149 ]  Patients suspected of having an acute DVT are often referred to the emergency department for evaluation. [ 150 ]   Interventional radiology  is the specialty that typically places and retrieves IVC filters, [ 151 ]  and vascular surgery might do catheter directed thrombosis for some severe DVTs. [ 147 ]


For the  prevention of blood clots  in the general population, incorporating leg exercises while sitting down for long periods, or having breaks from a sitting position and walking around, having an active lifestyle, and maintaining a healthy body weight are recommended. [ 6 ]  Walking increases blood flow through the leg veins. [ 152 ]  Excess body weight is modifiable unlike most risk factors, and interventions or lifestyle modifications that help someone who is overweight or obese  lose weight  reduce DVT risk. [ 88 ]  Avoiding both smoking and a  Western pattern diet  are thought to reduce risk. [ 153 ]  Statins have been investigated for  primary prevention  (prevention of a first VTE), and the  JUPITER trial , which used  rosuvastatin , has provided some tentative evidence of effectiveness. [ 14 ] [ 154 ]  Of the statins, rosuvastatin appears to be the only one with the potential to reduce VTE risk. [ 155 ]  If so, it appears to reduce risk by about 15%. [ 153 ]  However, the  number needed to treat  to prevent one initial VTE is about 2000, limiting its applicability. [ 156 ]


Acutely ill hospitalized patients are suggested to receive a parenteral anticoagulant, although the potential net benefit is uncertain. [ 63 ]  Critically ill hospitalized patients are recommended to either receive unfractionated heparin or low-molecular weight heparin instead of foregoing these medicines. [ 63 ]


Major orthopedic surgery— total hip replacement ,  total knee replacement , or  hip fracture surgery —has a high risk of causing VTE. [ 157 ]  If prophylaxis is not used after these surgeries, symptomatic VTE has about a 4% chance of developing within 35 days. [ 158 ]  Following major orthopedic surgery, a blood thinner or aspirin is typically paired with  intermittent pneumatic compression , which is the preferred mechanical prophylaxis over graduated compression stockings. [ 7 ]


Options for VTE prevention in people following non-orthopedic surgery include early walking, mechanical prophylaxis, and blood thinners (low-molecular-weight heparin and low-dose-unfractionated heparin) depending upon the risk of VTE, risk of major bleeding, and person's preferences. [ 159 ]  After low-risk surgeries, early and frequent walking is the best preventive measure. [ 7 ]


The risk of VTE is increased in pregnancy by about four to five times because of a more hypercoagulable state that protects against fatal  postpartum hemorrhage . [ 28 ]  Preventive measures for pregnancy-related VTE were suggested by the  American Society of Hematology  in 2018. [ 160 ]  Warfarin, a common vitamin K antagonist, can cause birth defects and is not used for prevention during pregnancy. [ 161 ]


Travelling "is an often cited yet relatively uncommon" cause of VTE. [ 28 ]  Suggestions for at-risk [ n ]  long-haul travelers include calf exercises, frequent walking, and aisle seating in airplanes to ease walking. [ 162 ] [ 163 ]  Graduated compression stockings have sharply reduced the levels of asymptomatic DVT in airline passengers, but the effect on symptomatic DVT, PE, or mortality is unknown, as none of the individuals studied developed these outcomes. [ 164 ]  However, graduated compression stockings are not suggested for long-haul travelers (>4 hours) without risk factors for VTE. Likewise, neither aspirin nor anticoagulants are suggested in the general population undertaking long-haul travel. [ 63 ]  Those with significant VTE risk factors [ o ]  undertaking long-haul travel are suggested to use either graduated compression stockings or LMWH for VTE prevention. If neither of these two methods are feasible, then aspirin is suggested. [ 63 ]


DVT is most frequently a disease of older age that occurs in the context of nursing homes, hospitals, and active cancer. [ 3 ]  It is associated with a 30-day  mortality rate  of about 6%, with PE being the cause of most of these deaths. [ 1 ]  Proximal DVT is frequently associated with PE, unlike distal DVT, which is rarely if ever associated with PE. [ 39 ]  Around 56% of those with proximal DVT also have PE, although a chest CT is not needed simply because of the presence of DVT. [ 1 ]  If proximal DVT is left untreated, in the following 3 months approximately half of people will experience symptomatic PE. [ 9 ]


Another frequent complication of proximal DVT, and the most frequent chronic complication, is post-thrombotic syndrome, where individuals have chronic venous symptoms. [ 5 ]  Symptoms can include pain, itching, swelling,  paresthesia , a sensation of heaviness, and in severe cases,  leg ulcers . [ 5 ]  After proximal DVT, an estimated 20–50% of people develop the syndrome, with 5–10% experiencing severe symptoms. [ 165 ]  Post-thrombotic syndrome can also be a complication of distal DVT, though to a lesser extent than with proximal DVT. [ 166 ]


In the 10 years following an initial VTE, about 30% of people will have a recurrence. [ 3 ]  VTE recurrence in those with prior DVT is more likely to recur as DVT than PE. [ 167 ]  Cancer [ 5 ]  and unprovoked DVT are strong risk factors for recurrence. [ 60 ]  After initial proximal unprovoked DVT with and without PE, 16–17% of people will have recurrent VTE in the 2 years after they complete their course of anticoagulants. VTE recurrence is less common in distal DVT than proximal DVT. [ 44 ] [ 45 ]  In upper extremity DVT, annual VTE recurrence is about 2–4%. [ 130 ]  After surgery, a provoked proximal DVT or PE has an annual recurrence rate of only 0.7%. [ 60 ]


About 1.5 out of 1000 adults a year have a first VTE in high-income countries. [ 168 ] [ 169 ]  The condition becomes much more common with age. [ 3 ]  VTE rarely occurs in children, but when it does, it predominantly affects hospitalized children. [ 170 ]  Children in North America and the Netherlands have VTE rates that range from 0.07 to 0.49 out of 10,000 children annually. [ 170 ]  Meanwhile, almost 1% of those aged 85 and above experience VTE each year. [ 3 ]  About 60% of all VTEs occur in those 70 years of age or older. [ 9 ]  Incidence is about 18% higher in males than in females, [ 4 ]  though there are ages when VTE is more prevalent in women. [ 15 ]  VTE occurs in association with hospitalization or nursing home residence about 60% of the time, active cancer about 20% of the time, and a central venous catheter or transvenous pacemaker about 9% of the time. [ 3 ]


During pregnancy and after childbirth, acute VTE occurs in about 1.2 of 1000 deliveries. Despite it being relatively rare, it is a leading cause of maternal morbidity and  mortality . [ 160 ]  After surgery with preventive treatment, VTE develops in about 10 of 1000 people after total or partial knee replacement, and in about 5 of 1000 after total or partial hip replacement. [ 171 ]  About 400,000 Americans develop an initial VTE each year, with 100,000 deaths or more attributable to PE. [ 169 ]   Asian, Asian-American, Native American, and Hispanic individuals have a lower VTE risk than Whites or Blacks. [ 4 ] [ 15 ]  Populations in Asia have VTE rates at 15 to 20% of what is seen in Western countries, with an increase in incidence seen over time. [ 16 ]  In North American and European populations, around 4–8% of people have a thrombophilia, [ 89 ]  most commonly factor V leiden and prothrombin G20210A. For populations in China, Japan, and Thailand, deficiences in protein S, protein C, and antithrombin predominate. [ 172 ]  Non-O blood type is present in around 50% of the general population and  varies with ethnicity , and it is present in about 70% of those with VTE. [ 90 ] [ 173 ]


DVT occurs in the upper extremities in about 4–10% of cases, [ 11 ]  with an incidence of 0.4–1.0 people out of 10,000 a year. [ 5 ]  A minority of upper extremity DVTs are due to Paget–Schroetter syndrome, also called effort thrombosis, which occurs in 1–2 people out of 100,000 a year, usually in athletic males around 30 years of age or in those who do significant amounts of overhead manual labor. [ 69 ] [ 147 ]


Being on blood thinners because of DVT can be life-changing because it can prevent lifestyle activities such as contact or winter sports to prevent bleeding after potential injuries. [ 175 ]  Head injuries prompting brain bleeds are of particular concern. This has caused NASCAR driver  Brian Vickers  to forego participation in races. Professional basketball players including NBA players  Chris Bosh  and hall of famer  Hakeem Olajuwon  have dealt with recurrent blood clots, [ 176 ]  and Bosh's career was significantly hampered by DVT and PE. [ 177 ]


Tennis star  Serena Williams  was hospitalized in 2011 for PE thought to have originated from DVT. [ 178 ]  Years later, in 2017, due to her knowledge of DVT and PE, Serena accurately  advocated  for herself to have a PE diagnosed and treated. During this encounter with VTE, she was hospitalized after a  C-section  surgery and was off of blood thinners. After feeling the sudden onset of a PE symptom, shortness of breath, she told her nurse and requested  a CT scan  and an IV heparin drip, all while gasping for air. She started to receive an ultrasound to look for DVT in the legs, prompting her to express dissatisfaction to the medical staff that they were not looking for clots where she had symptoms (her lungs), and they were not yet treating her presumed PE. After being diagnosed with PE and not DVT, and after receiving heparin by IV, the coughing from the PE caused her C-section surgical site to open and the heparin contributed to bleeding at the site. Serena later received an IVC filter while in the hospital. [ 174 ] [ 179 ]


Other notable people have been affected by DVT. Former United States President  Richard Nixon  had recurrent DVT, [ 180 ]  and so has former Secretary of State  Hillary Clinton . She was first diagnosed while  First Lady  in 1998 and again in 2009. [ 181 ]   Dick Cheney  was diagnosed with an episode while  Vice President , [ 182 ]  and TV show host  Regis Philbin  had DVT after hip-replacement surgery. [ 183 ]  DVT has also contributed to the deaths of famous people. For example, DVT and PE played a role in rapper  Heavy D 's death at age 44. [ 184 ]  NBC journalist  David Bloom  died at age 39 while covering the Iraq War from a PE that was thought to have progressed from a missed DVT, [ 185 ]  and actor  Jimmy Stewart  had DVT that progressed to a PE when he was 89. [ 183 ] [ 186 ]


The book  Sushruta Samhita , an  Ayurvedic  text published around 600–900 BC, contains what has been cited as the first description of DVT. [ 187 ]  In 1271, DVT symptoms in the leg of a 20-year-old male were described in a French manuscript, which has been cited as the first case or the first Western reference to DVT. [ 187 ] [ 188 ]


In 1856, German physician and pathologist  Rudolf Virchow  published his analysis after the insertion of foreign bodies into the jugular veins of dogs, which migrated to the pulmonary arteries. These foreign bodies caused pulmonary emboli, and Virchow was focused on explaining their consequences. [ 189 ]  He cited three factors, which are now understood as hypercoagulability, stasis, and endothelial injury. [ 190 ]  It was not until 1950 that this framework was cited as Virchow's triad, [ 189 ]  but the teaching of Virchow's triad has continued in light of its utility as a theoretical framework and as a recognition of the significant progress Virchow made in expanding the understanding of VTE. [ 189 ] [ 190 ]


Methods to observe DVT by ultrasound were established in the 1960s. [ 120 ]  Diagnoses were commonly performed by  impedance plethysmography  in the 1970s and 1980s, [ 191 ]  but ultrasound, particularly after utility of probe compression was demonstrated in 1986, became the preferred diagnostic method. [ 187 ]  Yet, in the mid-1990s, contrast venography and impedance plethysmography were still described as common. [ 192 ]


Multiple pharmacological therapies for DVT were introduced in the 20th century: oral anticoagulants in the 1940s,  subcutaneous injections  of LDUH in 1962 and subcutaneous injections of LMWH in 1982. [ 193 ]  1974 was when vascular inflammation and venous thrombosis were first proposed to be interrelated. [ 112 ]  For around 50 years, a months-long warfarin (Coumadin) regimen was the mainstay of pharmacological treatment. [ 194 ] [ 195 ]  To avoid the blood monitoring required with warfarin and the injections required by heparin and heparin-like medicines,  direct oral anticoagulants  (DOACs) were developed. [ 195 ]  In the late 2000s to early 2010s, DOACs—including rivaroxaban (Xarelto), apixaban (Eliquis), and dabigatran (Pradaxa)—came to the market. [ 60 ]   The New York Times  described a "furious battle" among the three makers of these drugs "for the prescription pads of doctors". [ 194 ]


VTE costs the US healthcare system about $7 to 10 billion dollars annually. [ 169 ]  Initial and average DVT costs for a hospitalized US patient is about $10,000 (2015 estimate). [ 196 ]   In Europe, the costs for an initial VTE hospitalization are significantly less, costing about  € 2000 to 4000 (2011 estimate). [ 197 ]  Post-thrombotic syndrome is a significant contributor to DVT follow-up costs. [ 198 ]  Outpatient treatment significantly reduces costs, and treatment costs for PE exceed those of DVT. [ 199 ]


A 2019 study published in  Nature Genetics  reported more than doubling the known  genetic loci  associated with VTE. [ 14 ]  In their updated 2018 clinical practice guidelines, the  American Society of Hematology  identified 29 separate research priorities, most of which related to patients who are acutely or critically ill. [ 63 ]  Inhibition of  factor XI ,  P-selectin ,  E-selectin , and a reduction in formation of  neutrophil extracellular traps  are potential therapies that might treat VTE without increasing bleeding risk. [ 200 ]


Cited literature


The haemostatic (blood clotting) system involves the interaction of proteins in the blood, the blood vessel wall and the flow of blood to control bleeding and  blood clotting .  Developmental  Haemostasis  is a term that represents the maturation of the haemostatic system from birth to adulthood. There are differences in the concentration, structure and activity of many proteins involved in blood clotting. [ 1 ] [ 2 ]  These changes play an important role in physiological development and are important in providing appropriate diagnosis and treatment of bleeding and clotting disorders (e.g.  thrombosis ). [ 3 ] [ 4 ]  The age-specific differences in the blood clotting system may contribute to the fact that children are less prone to developing thrombosis compared to adults. [ citation needed ]


Studies have shown that there are structural differences in some of the major blood clotting proteins in newborns and children when compared to adults. [ 5 ] [ 6 ] [ 7 ]  These structural differences can lead to differences in the activity of haemostatic proteins within the blood clotting system, as well as other physiological systems (e.g. immune system).


Some examples of age-specific differences in the structure of blood clotting proteins are: [ citation needed ]


Reference ranges  demonstrate the normal test values for a healthy population. Diseases and disorders are diagnosed when a test value is outside the reference range. Many laboratories compare paediatric results to adult reference ranges or to published paediatric reference ranges that may not be specific for the test used. [ 11 ]  This can lead to misdiagnosis or over-diagnosis of blood clotting disorders as many proteins exist at levels during stages of infancy that would be associated with disease in adults. This can lead to unnecessary stress for families and can have significant medical implications for the child (e.g. further testing).
The differences in the haemostatic proteins can lead to different interactions with  anticoagulant  drugs that are used to prevent and treat thrombosis in children. [ 12 ] [ 13 ]  More studies are required to determine the optimal treatment strategies and doses of anticoagulants in children. [ citation needed ]


The role of developmental haemostasis in normal physiology is still not fully understood. It has been observed that the newborn haemostatic system is protective and contributes to a decreased risk of bleeding or thrombosis compared to adults. The differences may also be due to the role haemostatic proteins play within other physiological systems. [ citation needed ]


Divicine  (2,6-diamino-4,5-dihydroxypyrimidine) is an oxidant and a base with alkaloidal properties found in  fava beans  and  Lathyrus sativus . It is an  aglycone  of  vicine . A common derivative is the diacetate form (2,6-diamino-1,6-dihydro-4,5-pyrimidinedione). [ 1 ]


Divicine is found in  fava beans  and in the legume  Lathyrus sativus , also known as khesari, which is a cheap and robust food source commonly grown in Asia and East Africa. [ citation needed ]


In plants, reduced divicine is formed from the hydrolysis of the inactive β–glucoside,  vicine . [ 2 ]


A simplified three-step process for artificial divicine synthesis:


Some chemical characteristics of divicine have been examined. It is known that it vigorously reduces  alkaline  solutions of 2,6-dichlorophenolindophenol, phosphomolybdate or phosphotungstate and produces an intense blue colour when reacting with an ammoniacal ferric chloride solution, which is used for the identification and proof of the presence of an enolic  hydroxyl  group.


Divicine is very unstable if oxygen is present and the oxidation is most rapid at alkaline pH levels. The half-life of divicine, at room temperature and neutral pH, is around half an hour. Both compounds are almost immediately destroyed by boiling, and breakdown in regular conditions can be accelerated by the presence of heavy metal ions, especially Cu 2+ . [ 4 ]


Divicine has been deemed a  hemotoxic  component of  fava beans  and plays a role in the development of  favism , a disorder that involves a hemolytic response to the consumption of broad beans due to  glucose-6-phosphate dehydrogenase  (G6PD or G6PDH) deficiency.  This deficiency, an X-linked recessive hereditary disease, is the most common enzyme deficiency worldwide.  It is particularly common in those of African, Asian, Mediterranean, and Middle-Eastern descent.  Symptoms of  favism  include  hemolysis , prolonged  jaundice ,  kernicterus , and even  acute renal failure  in extreme cases. [ 5 ]


Divicine reacts with oxygen in red blood cells, which creates  reactive oxygen species  such as  hydrogen peroxide  and  superoxide anion . These molecules are strong oxidizers of  NADPH  and  glutathione . [ 6 ]  G6PD deficient individuals cannot regenerate NADPH quickly enough to prevent depletion of glutathione. This depletion results in the cells having no protection against oxidative stress caused by the aglycones. Oxidative stress leads to damage of haemoglobin and disulphide bond aggregates ( Heinz bodies ), which result in haemolytic anaemia, called favism. [ 7 ]


Divicine is also present in and at least partially responsible for the poisonous action of  Lathyrus sativus  - a legume commonly grown in drought- and famine-prone regions of Asia and East Africa as an ‘insurance crop’ for human consumption and livestock feed when other crops fail to grow, despite their known health hazards. [ citation needed ]


In vitro studies in rats showed that a hemotoxic dose of divicine of 1.5 mM, when added to a suspension of red blood cells, resulted in a rapid decline in cellular glutathione, formation of  echinocytes  and damage to the membrane skeleton. This resulted in a decrease in  haematocrit . [ 8 ]


Duteplase  is a  plasminogen activator . [ 1 ]


Effective arterial blood volume  (EABV) refers to the adequacy of the arterial blood volume to "fill" the capacity of the  arterial vasculature . Normal EABV exists when the ratio of cardiac output to peripheral resistance maintains venous return and cardiac output at normal levels. EABV can be reduced, therefore, by factors which reduce actual arterial blood volume (hemorrhage, dehydration), increase arterial vascular capacitance (cirrhosis, sepsis) or reduce cardiac output (congestive heart failure). EABV can be reduced in the setting of low, normal, or high actual blood volume. Whenever EABV falls, the kidney is triggered to retain sodium and water. [ 1 ]


In cases of  edema , increases in  extracellular fluid  (ECF) is associated with a corresponding decrease in EABV.  The kidneys detect changes in EABV and through Na +  excretions, they attempt to restore EABV balance.  The kidney mechanisms used to restore EABV include, (1) increased  sympathetic  nerve activity; (2) decreased  Atriopeptin  (ANP) secretion from the atria; (3) increased  oncotic pressure  ( Starling forces ); (4) increased activity of the  Renin–angiotensin–aldosterone system . [ 2 ]


Elliptocytes , also known as  ovalocytes  or  cigar cells , are abnormally shaped red blood cells that appear oval or elongated, from slightly egg-shaped to rod or pencil forms. They have normal central pallor with the hemoglobin appearing concentrated at the ends of the elongated cells when viewed through a  light microscope . The ends of the cells are blunt and not sharp like  sickle cells . [ 1 ]


Elliptocytes are commonly associated with  hereditary elliptocytosis . However, they may also be seen in  iron deficiency anemia ,  sepsis ,  malaria  and other pathological states that decrease red blood cell turnover and or production. [ 2 ]  In the case of iron deficiency anemia,  microcytosis  and  hypochromia  would also be expected. [ 3 ]


Rare elliptocytes (less than 1%) on a  peripheral blood smear  are a normal finding. [ citation needed ]


These abnormal red blood cells are seen in higher numbers in the  blood films  of patients with  blood disorders  such as: [ 4 ]


An  embolism  is the lodging of an  embolus , a blockage-causing piece of material, inside a  blood vessel . [ 1 ]  The embolus may be a blood clot ( thrombus ), a fat globule ( fat embolism ), a bubble of air or other gas ( gas embolism ),  amniotic fluid  ( amniotic fluid embolism ), or  foreign material .


An embolism can cause partial or total blockage of  blood flow  in the affected vessel. [ 2 ]  Such a blockage ( vascular occlusion ) may affect a part of the body distant from the origin of the embolus. An embolism in which the embolus is a piece of thrombus is called a  thromboembolism .


An embolism is usually a pathological event, caused by illness or injury. Sometimes it is created intentionally for a therapeutic reason, such as to  stop bleeding  or to kill a cancerous tumor by stopping its blood supply. Such therapy is called  embolization .


There are different types of embolism, some of which are listed below.


Embolism can be classified based on where it enters the circulation, either in  arteries  or in  veins . Arterial embolism are those that follow and, if not dissolved on the way, lodge in a more distal part of the  systemic circulation . Sometimes, multiple classifications apply; for instance a  pulmonary embolism  is classified as an arterial embolism as well, [ 3 ]  because the clot follows the  pulmonary artery  carrying deoxygenated blood away from the heart. However, pulmonary embolism is generally classified as a form of venous embolism, because the embolus forms in veins, e.g.  deep vein thrombosis . [ citation needed ]


Arterial embolism  can cause occlusion in any part of the body. It is a major cause of  infarction  (tissue death from blockage of the blood supply). [ 4 ]


An embolus lodging in the brain from either the  heart  or a  carotid artery  will most likely be the cause of a  stroke  due to  ischemia . [ 5 ]


An arterial embolus might originate in the heart (from a thrombus in the  left atrium , following  atrial fibrillation  or be a septic embolus resulting from  endocarditis ). Emboli of  cardiac origin  are frequently encountered in clinical practice.  Thrombus formation within the atrium occurs mainly in patients with  mitral valve  disease, and especially in those with  mitral valve   stenosis  (narrowing), with  atrial fibrillation  (AF).  In the absence of AF, pure mitral regurgitation has a low incidence of  thromboembolism . [ citation needed ]