Platelet transfusion thresholds for more major procedures are based on expert opinion alone. [ 25 ]  Guidelines recommend a threshold of 50 x 10 9 /L for major surgery and a threshold of 100 x 10 9 /L for surgery on the brain or the back of the eye. [ 10 ] [ 13 ] [ 11 ]  Platelet transfusion may be indicated for patients with spontaneous intracerebral hemorrhage to reverse aspirin effect if they require emergency
neurosurgery, but not if they are managed without surgery. [ 26 ]


There is little evidence for the effectiveness of platelet transfusions or the optimal dose when a person with a low platelet count is actively bleeding. Current recommendations are based on consensus guidelines from around the world. [ 10 ] [ 9 ]


Side effects can include  allergic reactions  such as  anaphylaxis ,  infection , and  lung injury . [ 2 ]   Bacterial infections  are relatively more common with platelets as they are stored at warmer temperatures. [ 2 ]


People with hematological disorders or  cancer  receive the largest proportion of platelet transfusions. [ 27 ] [ 28 ] [ 29 ]  Most are given to prevent bleeding during treatment with  chemotherapy  or  stem cell transplant . [ 29 ] [ 28 ] [ 30 ]  Much of the remainder are used in general medicine,  cardiac surgery  and in  intensive care . [ 29 ] [ 28 ] [ 30 ]


Unlike other blood products demand for platelet transfusions appears to be increasing in several countries around the world. [ 27 ]  An ageing population, an increase in the number of people with  blood cancer , and changes to the management of these cancers are likely the major reasons for the rise in demand for platelets. [ 27 ]  Since 1990, the number of stem cell transplants performed in Europe has risen from 4,200 to over 40,000 annually. [ 31 ]


Platelet transfusions came into medical use in the 1950s and 1960s. [ 1 ]  It is on the  World Health Organization's List of Essential Medicines . [ 6 ]


In the United Kingdom it costs the NHS about 200 pounds per unit. [ 32 ]


Platelets can be produced either from  whole blood  donations or by  apheresis . [ 1 ]  They keep for up to five to seven days. [ 1 ]


Platelet components can have had the  white blood cells  partially removed (leucodepleted) which decreases the risk of having a transfusion reaction. [ 33 ]  They can be treated with ultraviolet light which decreases the risk of transmission of certain infections. [ 34 ]  They can be  gamma irradiated  which have specific benefits for certain populations (those at risk of  transfusion-associated graft versus host disease ). [ 8 ]


Platelet transfusion refractoriness  is the repeated failure to achieve the desired level of  blood platelets  in a patient following a platelet  transfusion . The cause of refractoriness may be either  immune  or non-immune. Among immune-related refractoriness, antibodies against  HLA antigens  are the primary cause.  Non-immune causes include  splenomegaly  (enlargement of the spleen),  fever , and sepsis. [ 1 ] [ 2 ]


Platelet refractoriness can be due to immune causes or non-immune causes. [ 3 ]  Non-immune causes account for over 80% of cases of platelet refractoriness, and sepsis is one of the most common non-immune causes. [ 2 ] [ 3 ] [ 4 ] [ 5 ]   HLA   alloimmunization  is the commonest immune cause of platelet refractoriness. [ 2 ] [ 3 ] [ 4 ] [ 5 ]


Platelet transfusion refractoriness can be defined in several different ways. All measures of platelet refractoriness are defined by the timing of the post-transfusion platelet count, usually 1 hour post transfusion or 24 hours post transfusion or both. [ 2 ] [ 9 ]


This is the simplest method, and only requires data on the platelet count before and after the transfusion. [ 9 ]  The platelet increment is also known as the  absolute count increment  and  count increment . [ 5 ] [ 10 ]


PI = post-transfusion platelet count - pre-transfusion platelet count


However, it is affected by the number of platelets given in the transfusion (platelet dose) and the patient's blood volume. Larger patients and smaller platelet doses decrease the platelet increment. [ 2 ] [ 9 ]  These factors are adjusted for in the other methods of defining platelet refractoriness. [ 2 ] [ 3 ] [ 9 ]


A 1-hour post-transfusion PI of less than 5 to 10 x 10 9 /l is considered evidence of platelet refractoriness. [ 5 ] [ 10 ]  Due to lack of data on platelet dose this is often the only measure of platelet refractoriness that can be performed in routine clinical practice. [ 5 ]


Requires data on the platelet increment (PI), the patient's total blood volume (TBV) - estimated using the patient's weight multiplied by 0.075, and the number of platelets transfused (platelet dose) [ 10 ] [ 11 ]


PPR = ((PI x TBV)/PD) x 100


At 1 hour post-transfusion, a PPR < 20% is considered evidence of platelet refractoriness. [ 5 ] [ 10 ]  At 16 hours post-transfusion a PPR < 10% is considered evidence of platelet refractoriness. [ 10 ]


PPI is very similar to the percentage platelet recovery (PPR) but there has been an additional adjustment for splenic pooling of platelets (PPR multiplied by 2/3) [ 5 ] [ 11 ]


PPI = PPR/0.67 = ((PI / 0.67) x TBV)/PD x 100


This requires data on the platelet increment (PI, in platelets/μL), the patient's  Body surface area  (BSA, in m 2 ), and the number of platelets transfused (PD, in 10 11 ). [ 5 ] [ 10 ] [ 11 ]


C
 C
 I

 =
 P
 I
 ∗

 B
 S
 A

 P
 D

 {\displaystyle {CCI}=PI*{\frac {BSA}{PD}}}


For example, a PI of 25,000 platelets/μL, a BSA of 1.8m 2  and a PD of 4x10 11  gives a CCI of 11,250 platelets*m 2 /10 11 μL


At 1 hour post-transfusion a CCI greater than 7500 indicates a sufficient post-transfusion increment, whereas a CCI less than 7500 is considered diagnostic of platelet refractoriness. [ 10 ]  At 24 hours post transfusion a CCI less than 5000 suggests platelet refractoriness. [ 10 ]


Some blood banks maintain records of the estimated number of platelets in each unit. [ 5 ]  Current requirements in the US stipulate that a unit of apheresis platelets must contain at least 3.0 x10 11  platelets. [ 12 ]  In England only 1% of adult platelet components are tested to check the number of platelets meet the minimum required standard of 2.4 x 10 11  platelets. [ 13 ] [ 14 ]  Only components that contain fewer than 1.6 x 10 11  platelets are discarded. [ 13 ] [ 14 ]  This means that there can be a lot of variability in the number of platelets contained within each transfusion. [ 5 ]


Treatment depends on the underlying cause. [ 15 ]


Non-immune causes are usually treated by treating the underlying cause e.g.  sepsis . [ 3 ] [ 16 ]


If there is no obvious non-immune cause, a first step can be to use platelet components that are likely to produce the greatest platelet increment (less than 3 days old and ABO-matched), while further investigations are performed (testing for HLA antibodies). [ 3 ] [ 4 ]


If an immune cause is suspected and  HLA antibodies are detected, then HLA-selected platelet components can be used. [ 3 ] [ 4 ]  Although HLA-selected platelets lead to improved platelet increments at 1 hour post-transfusion, [ 17 ]  there is currently insufficient evidence to demonstrate their clinical effectiveness at preventing bleeding. [ 17 ]


If HLA antibodies are not detected, and HPA antibodies are detected, then HPA-selected or crossmatched platelet components can be used. [ 3 ] [ 7 ] [ 16 ]


HLA and HPA-selected components should not be used if no HLA or HPA antibodies are detected. [ 16 ]


Other strategies for managing patients with platelet refractoriness who require procedures include  thrombopoietin receptor agonists , [ 18 ]  complement inhibitors such as  eculizumab , [ 19 ]  and slow infusion. [ 20 ]


Platelet-Poor Plasma  ( PPP ) is  blood plasma  with very  low number of platelets  (< 10 X 10 3 /μL).  Traditionally, PPP was recommended for use in  platelet  aggregation studies to both adjust the  platelet-rich plasma  concentration, and to serve as a control. [ 1 ]   PPP may have elevated levels of  fibrinogen , which has the ability to form a fibrin-rich clot once activated.  Wound healing requires cell migration and attachment, which is facilitated by this fibrin clot. [ 2 ]


Fibrin sealants have found use in many clinical situations such as blood management, [ 3 ]  orthopaedic surgery, [ 4 ]  and cosmetic surgery. [ 5 ]


As a byproduct of PRP preparation, PPP may also find use in tissue engineering applications as an  autologous  degradable scaffold.  This plasma portion is frequently discarded when used with PRP treatments. [ 6 ]


Platelet-rich fibrin  ( PRF ) or  leukocyte- and platelet-rich fibrin  ( L-PRF ) is a derivative of  PRP  where  autologous   platelets  and leukocytes are present in a complex fibrin matrix [ 1 ] [ 2 ]  to accelerate the healing of soft and hard tissue [ 3 ]  and is used as a tissue-engineering scaffold in oral and maxillofacial surgeries. PRF falls under FDA Product Code KST, labeling it as a blood draw/Hematology product classifying it as 510(k) exempt.


To obtain PRF, the required quantity of blood is drawn into test tubes without an anticoagulant and centrifuged immediately. Blood can be centrifuged using a tabletop centrifuge from 3-8 minutes for 1300 revolutions per minute. The resultant product consists of the following three layers: the topmost layer consisting of platelet poor plasma, the PRF clot in the middle, and the red blood cells (RBC) at the bottom. The PRF clot can be removed from the test tube using a pickup instrument (such as Gerald tissue forceps). The RBC layer attached to the PRF clot can be carefully removed using scissors or a blunt instrument. [ 4 ]


Platelet activation in response to tissue damage occurs during the process of making PRF release several biologically active proteins including; platelet alpha granules, platelet‑derived growth factor (PDGF), transforming growth factors‑β (TGF‑β), vascular endothelial growth factor (VEGF), and epidermal growth factor. [ 5 ]  Actually, the platelets and leukocyte cytokines play important parts in role of this biomaterial, but the fibrin matrix supporting them is the most helpful in constituting the determining elements responsible for real therapeutic potential of PRF. Cytokines are immediately used and destroyed in a healing wound. The harmony between cytokines and their supporting fibrin matrix has much more importance than any other platelet derivatives. [ 6 ]


Ridge preservation (Colloquially  Socket preservation ), a procedure to reduce bone loss after  tooth extraction  to preserve the  dental alveolus  (containing the tooth socket) in the  alveolar bone . A platelet-rich fibrin (PRF) membrane containing bone growth enhancing elements can be stitched over the wound or a graft material or scaffold is placed in the socket of an extracted tooth at the time of extraction. The socket is then directly closed with stitches or covered with a non-resorbable or resorbable membrane and  sutured . [ citation needed ]


A platelet-rich fibrin can be used if a  sinus lift  is required for a  dental implant . [ 7 ] [ 8 ]


Reproduction or reconstitution of a lost or injured part to restore the architecture and function of the periodontium becomes the integral part of comprehensive periodontal therapy. Conventional  open flap debridement  falls short of regenerating tissues destroyed by the disease.  Platelet derived growth factor  along with bone morphogenetic proteins are among the most researched growth factors in periodontal regeneration. [ 9 ] [ 10 ]  Platelet rich fibrin showed significant improvement in clinical periodontal parameter as well as in radiograph when compared with open flap debridement alone in a  meta analysis . [ 11 ]  Several bone graft materials have been used in the treatment of infrabony defects.  Demineralized freeze dried bone allograft  (DFDBA) has been histologically proven to be the material of choice for regeneration. Platelet-rich fibrin has shown significant results comparable to DFDBA for periodontal regeneration. [ 12 ]  One of the most common aesthetic problem encountered in the field of periodontology is gingival recession, which is perceived by the patients as increase in length of teeth. Though connective tissue graft is a gold standard procedure, PRF can be used as an alternative procedure by keeping patient's comfort in mind. [ 13 ]


PRF is used in  guided bone and tissue regeneration . [ 14 ]


PRF enhances  alveolar bone augmentation [ 15 ]  and  necrotic  dental pulp  and open  tooth apex  can be revitalized in  regenerative endodontics  with platelet-rich fibrin. [ 16 ]


Platelet-rich plasma  ( PRP ), also known as  autologous conditioned plasma , is a concentrate of  plasma protein  derived from whole  blood ,  centrifuged  to remove  red blood cells  but retaining  platelets . Though promoted for treating various medical conditions, evidence of its benefits was mixed as of  2020 , showing effectiveness in certain conditions and ineffectiveness in others. [ 1 ] [ 2 ] [ 3 ]


As a concentrated source of  blood plasma  and autologous conditioned plasma, PRP contains multiple  growth factors  and other  cytokines  that can stimulate the healing of  soft tissues  and  joints . Indications for its use include  sports medicine  and  orthopaedics  (such as acute muscle strains, tendinopathy,tendinosis, muscle-fascial injuries, and osteoarthritis, [ 4 ] )  dermatology  (for  androgenic alopecia ,  wound healing , and  skin rejuvenation ), and even  proctology  (for  fistula en ano [ 5 ] ). [ 6 ]


Various preparation protocols exist, with the underlying principle of concentrating platelets to 3–5 times physiological levels, then injecting this concentrate into the  tissue  where  healing  is desired. [ 7 ]  Beyond clinical practice, PRP has been utilized in various  tissue engineering  applications involving  bone ,  cartilage ,  skin , and soft tissue repair. It serves as a source for the delivery of growth factors and/or cells within tissue-engineered constructs, often in combination with  biomaterials .
 [ 8 ]


Evidence for benefit of PRP is mixed, with some evidence for use in certain conditions and against use in other conditions. [ 9 ] [ 10 ] [ 3 ]  It has been investigated for chronic  tendinitis , [ 11 ]   osteoarthritis , [ 12 ]  in  oral surgery , [ 13 ]  and in  plastic surgery . [ 14 ]


A 2022 study from the Journal of Clinical Medicine compared PRP injections to physical therapy. They found that PRP significantly lowered pain scores and increased elbow function. [ 15 ]  A 2022 study considered PRP for elbow tendinopathy. They found that PRP was effective and that the concentration of the platelets and healing factors such as epidermal growth factor (EGF) were correlated with success of treatment. [ 16 ]


A 2022 meta-analysis reviewed 26 studies on PRP for elbow tendinopathy. They found that PRP-treated patients rated their results significantly better using validated patient rated outcomes measures. [ 17 ]  A 2021 systematic review by the  Cochrane Library  examined PRP and autologous whole blood injections and concluded that it was "uncertain" if PRP or autologous whole blood injections improved elbow tendon healing. [ 18 ]


A 2018 systematic review and meta-analysis of high quality studies found that PRP was beneficial for treatment of  lateral epicondylitis . [ 19 ]


Numerous reviews and meta-analyses have found that for elbow tendinopathy, PRP is superior to  cortisone  injections. [ 20 ] [ 21 ] [ 22 ] [ 23 ] [ 24 ]  It has been shown to have similar [ 25 ]  or equal [ 26 ] [ 27 ]  effects compared to surgery.


A 2022 review and meta-analysis showed improved patient-rated outcomes in patients with partial  rotator cuff  tears. At 8 weeks post injection, they found PRP to be effective. [ 28 ]  A 2021 prospective study examined the effectiveness of PRP for partial thickness rotator cuff tears. Patients were given 2 separate PRP injections and followed for 2 years. The study noted: “No adverse events were seen in any patient. Based on global rating scores positive results were seen in 77.9 % of patients at 6 months, 71.6 % at 1 year, and 68.8 % of patients at 2 years”. They found PRP most effective in more damaged tendons. [ 29 ]  A 2021 meta-analysis found that PRP was effective for partial rotator cuff tears but the effects were no longer evident at 1 year. [ 30 ]


PRP has been shown to be superior to cortisone injections in several studies. [ 31 ]  This is especially evident in the longer term. [ 32 ] [ 33 ]


A 2019 review found it not to be useful in  rotator cuff disease . [ 3 ]  A 2018 review found that it may be useful. [ 19 ]  A 2009 review found few randomized controlled trials that adequately evaluated the safety and efficacy of PRP treatments and concluded that PRP was "a promising, but not proven, treatment option for joint, tendon, ligament, and muscle injuries". [ 34 ]


Tentative evidence supports the use of PRP in  osteoarthritis  of the knee. [ 35 ] [ 36 ]  A 2019 meta-analysis found that PRP might be more effective in reducing pain and improving function than  hyaluronic acid  in knee arthritis. [ 37 ]


A 2022 review found that in people with  meniscus tears , PRP treatment reduced the failure rate of meniscus repair surgery and reduced postoperative pain. However, the review did not find consistent evidence that PRP improved knee function. [ 38 ]


Platelet-rich plasma  (PRP) is an emerging technique in tissue regeneration, increasingly used to enhance healing in dental and  oral surgery , particularly for aging patients. PRP is derived from the patient's blood through  centrifugation , concentrating growth factors that are crucial for wound healing and tissue repair.


Tooth Extractions and Periodontal Surgery:  PRP application in the alveolar socket after  tooth extractions  improves soft tissue healing and positively affects bone regeneration, although the effect on bone tends to diminish after a few days.
In periodontal therapy, PRP yields better results when combined with other materials compared to its use alone.


Implant Surgery:
PRP has shown promising outcomes when used as a coating material in implant procedures, enhancing the  healing process.


Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) :
Combining necrotic bone curettage with PRP application has been effective for treating refractory BRONJ, offering successful outcomes with minimal  invasiveness .
 [ 39 ]


A 2014 Cochrane review of musculoskeletal injuries found very weak evidence for a decrease in pain in the short term, and no difference in function in the short, medium or long term. It has not been shown to be useful for bone healing. [ 40 ]  A 2016 review of bone graft augmentation found only one study reporting a difference in bone augmentation, while four studies found no difference. [ 41 ]  As compared to other conservative treatments for non-surgical orthopedic illnesses (e.g. steroid injection for  plantar fasciitis ), evidence does not support the use of PRP as a conservative treatment. [ 42 ]  A 2018 review found that evidence was lacking for  Achilles tendinopathy . [ 43 ]  A 2019 meta-analysis found that, for most outcomes in Achilles tendinopathy, PRP treatment did not differ from placebo treatment. [ 44 ]  A 2019 study conducted an umbrella review that "considered studies that included populations with differing levels of physical activity, including studies on the sporting population (professional and/or recreational athletes) and studies didn't explicitly mention involving a sporting population." This inquiry reported only poor quality evidence that PRP offers any clinical benefits for treatment in acute muscle, tendon, and ligament injuries in any population. [ 45 ]


Studies have reported that PRP is beneficial for  alopecia areata [ 46 ]  and  androgenetic alopecia  and can be used as an alternative to  minoxidil  or  finasteride . [ 47 ]  A review reported it to improve hair density and thickness in both genders. [ 48 ]  A minimum of 3 treatments, once a month for 3 months are recommended, and afterwards a 3-6 month period of continual appointments for maintenance. [ 49 ]  Factors that determine efficacy include number of sessions, double versus single centrifugation, age and gender, and where  insertion site. [ 50 ]


PRP can be inoculated into the  uterine cavity , to improve endometrial receptivity in cases of refractory  endometrium . Studies have reported that intrauterine inoculation of PRP before embryo transfer can thicken the endometrium and improve reproductive prognosis. [ 51 ]  PRP has been studied for the management of  Asherman's Syndrome . [ 52 ]


PRP can be inoculated experimentally into the  ovary  to promote ovarian tissue regeneration. The main applications would be in cases of diminished  ovarian reserve  or  premature ovarian failure . [ 53 ]


A 2023 retrospective observational study reported PRP's effectiveness in rejuvenating ovarian fertility and viability in terms of "the influence of intraovarian injection of autologous PRP on the levels of  E2 ". [ 53 ]  and pregnancy outcome in women treated with PRP who had a history of infertility, hormonal abnormalities, an absence of menstrual cycle, and premature ovarian failure in a single centre." [ 53 ]


A 2024 review showed that PRP is beneficial when used as intraovarian injections for women with decreased fertility. PRP used for fertility trouble increases AFC, [ 54 ]  number of  cleavage embryos , and improves cancellation rate in women with  poor ovarian reserve . However, "Although there was an improvement of baseline hormones ( anti-Müllerian hormone ,  follicle-stimulating hormone , and estradiol) after intraovarian injection of PRP, this improvement failed to reach statistical significance (except the improvement of serum AMH analyzed in quasi-experimental studies)." [ 55 ]


Venous ulcers  are persistent ankle or lower leg wounds that become open. [ 56 ]  A 2024 meta-analysis reported a positive effect on the size of ulcers as well as complete healing time for venous ulcers compared to standard treatments. A study combining a PRP therapy with conventional venous ulcer treatments reported improved quality of life and healing time. "In terms of safety, the recurrence rate in the PRP group was significantly lower than that in the control group, while the rates of infection and irritative dermatitis showed no significant difference from the control group." [ 57 ]


A 2024 meta-analysis reported that the growth factors present in PRP are vital in the healing of  diabetic foot ulcers ; specifically in their closure. The
treatments were reported to significantly increase the healing rate in comparison to conventional treatments. [ 58 ]


Platelet-rich plasma therapy is a  minimally invasive procedure  that may be used in  aesthetic medicine  to treat skin conditions such as the removal of  wrinkles , the reduction of lines, and improvement of blemishes, and  hair loss . Concentrated PRP solution is injected into the treatment area to target damaged cells and tissues. The growth factors and proteins in PRP aid in rejuvenating the skin, and improving the condition of the scalp stimulating hair growth. [ 59 ]


Adverse effects have been reported to be low in most trials. A review reported weak evidence of harm, occurring at comparable, low rates in treated and untreated people. [ 60 ] [ 18 ]


The three general categories of preparation of PRP based on  leukocyte  and  fibrin  content are leukocyte-rich PRP, leukocyte reduced PRP, and leukocyte platelet-rich fibrin. [ 7 ] [ 61 ]


The efficacy of certain growth factors in healing various injuries and the concentrations of these growth factors found within PRP are the theoretical basis for the use of PRP in tissue repair. [ 62 ]  Though not required for the process, platelets can be activated by the addition of  thrombin  or  calcium chloride , which induce the release of the factors from  alpha granules . The addition of thrombin or calcium chloride is not required as natural thrombin activates the cells upon injection. The growth factors and other cytokines present in PRP include: [ 62 ] [ 63 ] [ 64 ] [ 65 ]


PRP is prepared by taking blood from the person, and then putting it through  centrifugation  designed to separate PRP from  platelet-poor plasma  and  red blood cells . This is usually done in the clinic, using commercially available kits and equipment. [ 66 ]  The resulting substance varies from person to person and from facility to facility. [ 66 ] [ 67 ]


Use in an office setting is not approved by the  FDA . [ 68 ]


PRP has received attention in media [ 69 ] [ 70 ] [ 71 ]  as a result of its use by athletes. [ 72 ]


In the 2010s, cosmetic procedures marketed under the name of "vampire facials" grew in popularity, fueled by celebrity endorsement. These facials generally center on PRP treatment, and usually involve  microneedling . [ 73 ] [ 74 ]


In April 2024, the  CDC  announced that three women who had been patients at the Albuquerque, New Mexico, VIP Spa had been diagnosed with HIV after getting such facials. Another almost 200 former clients and their sexual partners tested negative. [ 75 ]


PRP has been injected into the  vagina , in a procedure called "O-shot [ 76 ] " or "orgasm shot", with claims to improve  orgasms . [ 77 ]  No evidence supports such claims. [ 77 ] [ 78 ]


PRP treatments may violate anti- doping  rules. [ 62 ]  As of 2010, it was not clear whether PRP could have a systemic impact on circulating  cytokine  levels, affecting doping tests and whether PRP treatments had systemic anabolic effects or affect performance. [ 62 ]  In January 2011, the  World Anti-Doping Agency  removed intramuscular injections of PRP from its prohibitions after determining that there is a "lack of any current evidence concerning the use of these methods for purposes of performance enhancement". [ 79 ]


In the early 1940s clinicians used extracts of growth factors and cytokines for healing. The term 'platet-rich plasma' was first used in 1954 by Kingsley and in the 1960s the first PRP blood banks were established, becoming popular by the 1970s. [ 80 ]  In the 1970s PRP was used in hematology, originally for transfusions to treat  thrombocytopenia . Ten years later it was used for maxillofacial surgeries. [ 6 ]  PRP was first used in Italy in 1987 in an open heart surgery procedure. [ 81 ]  In 2006 PRP was starting to be considered of potential use for both  androgenic alopecia  and  alopecia areata . [ 6 ]


Post-transfusion purpura  ( PTP ) is a delayed adverse reaction to a  blood transfusion  or  platelet transfusion  that occurs when the body has produced  alloantibodies  to the allogeneic transfused  platelets'   antigens . These alloantibodies destroy the patient's platelets leading to  thrombocytopenia , a rapid decline in platelet count. [ 1 ]  PTP usually presents 5–12 days after transfusion, and is a potentially fatal condition in rare cases. Approximately 85% of cases occur in women. [ 2 ]


PTP is rare, but usually occurs in women who have had multiple pregnancies or in people who have undergone previous transfusions.  The precise mechanism leading to PTP is unknown, but it most commonly occurs in individuals whose platelets lack the  HPA-1a  antigen (old name: PL A1 ).  The patient develops antibodies to the HPA-1a antigen leading to platelet destruction. In some cases, HPA-5b has also been implicated. It is unclear why alloantibodies attack the patient's own, as well as any transfused allogeneic random donor platelets. Probable explanation for this is that the recipient's platelets acquire the phenotype of donor's platelet by binding of the soluble antigens from the donor onto the recipient's platelet. [ 3 ]


Symptoms are usually sudden in onset and self-limiting, most often resolving within 2 weeks. [ 2 ]   IVIG  therapy is the primary treatment. [ 4 ]  Additionally, PTP is an  American Society for Apheresis  Category III indication for plasmapheresis. [ 5 ] [ 6 ]


Postpartum bleeding  or  postpartum hemorrhage  ( PPH ) is often defined as the loss of more than 500 ml or 1,000 ml of blood  following  childbirth . [ 2 ]  Some have added the requirement that there also be signs or symptoms of  low blood volume  for the condition to exist. [ 6 ]  Signs and symptoms may initially include: an  increased heart rate ,  feeling faint upon standing , and an increased breathing rate. [ 1 ]  As more blood is lost, the patient may feel cold, blood pressure may drop, and they may become restless or unconscious. [ 1 ]  In severe cases circulatory collapse,  disseminated intravascular coagulation  and death can occur. The condition can occur up to twelve weeks following delivery in the secondary form. [ 7 ]
The most common cause is  poor contraction of the uterus  following childbirth. [ 2 ]   Not all of the placenta being delivered , a tear of the  uterus , or poor  blood clotting  are other possible causes. [ 2 ]  It occurs more commonly in those who already have a  low amount of red blood , are  Asian , have a larger  fetus  or more than one fetus, are  obese  or are older than 40 years of age. [ 2 ]  It also occurs more commonly following  caesarean sections , those in whom medications are used to start labor, those requiring the use of a vacuum or  forceps , and those who have an  episiotomy . [ 2 ] [ 8 ]


Prevention involves decreasing known risk factors including procedures associated with the condition, if possible, and giving the medication  oxytocin  to stimulate the uterus to contract shortly after the baby is born. [ 2 ]   Misoprostol  may be used instead of oxytocin in resource-poor settings. [ 2 ]  Treatments may include: intravenous fluids,  blood transfusions , and the medication  ergotamine  to cause further uterine contraction. [ 2 ]  Efforts to compress the uterus using the hands may be effective if other treatments do not work. [ 2 ]  The  aorta  may also be compressed by pressing on the abdomen. [ 2 ]  The World Health Organization has recommended the  non-pneumatic anti-shock garment  to help until other measures such as surgery can be carried out. [ 2 ]   Tranexamic acid  has also been shown to reduce the risk of death, [ 3 ]  and has been recommended within three hours of delivery. [ 9 ]


In the  developing world  about 1.2% of deliveries are associated with PPH and when PPH occurred about 3% of women died. [ 2 ]  It is responsible for 8% of maternal deaths during childbirth in developed regions and 20% of maternal deaths during childbirth in developing regions. [ 7 ]  Globally it occurs about 8.7 million times and results in 44,000 to 86,000 deaths per year making it the leading cause of death during pregnancy. [ 4 ] [ 2 ] [ 10 ]  About 0.4 women per 100,000 deliveries die from PPH in the United Kingdom while about 150 women per 100,000 deliveries die in  sub-Saharan Africa . [ 2 ]  Rates of death have decreased substantially since at least the late 1800s in the United Kingdom. [ 2 ]


Depending on the source, primary postpartum bleeding is defined as blood loss in excess of 500 ml following  vaginal delivery  or 1000 mL following  caesarean section  in the first 24 hours following birth. Others have defined the condition as blood loss of greater than 1000 mL after either delivery method, or any amount of blood loss with signs and symptoms of hypovolemia. [ 7 ]  Secondary postpartum bleeding is that which occurs after the 24 hours up to 12 weeks after childbirth. [ 7 ]


Symptoms generally include heavy bleeding from the vagina that doesn't slow or stop over time. [ 11 ]  Initially there may be an  increased heart rate ,  feeling faint upon standing , and an increased respiratory rate. [ 1 ]  As more blood is lost, the patient may feel cold, blood pressure may drop, and they may become unconscious. [ 1 ]


Signs and symptoms of  circulatory shock  may also include blurry vision, cold and clammy skin, confusion, and feeling sleepy or weak. [ 1 ] [ 11 ]


Causes of postpartum hemorrhage are  uterine atony ,  trauma , retained  placenta  or  placental abnormalities , and  coagulopathy , commonly referred to as the "four Ts": [ 12 ]


Other risk factors include  endometriosis , [ 14 ]   obesity , fever during pregnancy, bleeding before delivery, and heart disease. [ 8 ]


Oxytocin  is typically used right after the delivery of the baby to prevent PPH. [ 2 ]   Misoprostol  may be used in areas where oxytocin is not available. [ 2 ]  Early clamping of the  umbilical cord  does not decrease risks and may cause  anemia  in the baby, and thus is usually not recommended. [ 2 ]


Active management of the third stage is a method of shortening the stage between when the baby is born and when the placenta is delivered. [ 15 ]  This stage is when the mother is at risk of having a PPH. Active management involves giving a drug which helps the uterus contract before delivering the placenta by a gentle but sustained pull on the umbilical cord whilst exerting upward pressure on the lower abdomen to support the uterus (controlled cord traction). [ 15 ]


Active management of the third stage of labor with uterotonics (oxytocin or Misoprostol) and gentle umbilical cord traction have been shown to reduce the incidence of PPH by 66%. [ 7 ]


Another method of active management which is no longer recommended is fundal pressure during the delivery of the placenta. A review into this method found no benefit to its use and advises only controlled cord traction because fundal pressure can cause the mother unnecessary pain. [ 15 ]  Allowing the cord to drain appears to shorten the third stage and reduce blood loss but evidence around this subject is not strong enough to draw solid conclusions. [ 16 ]


Nipple stimulation and breastfeeding triggers the release of natural oxytocin in the body, therefore it is thought that encouraging the baby to suckle soon after birth may reduce the risk of PPH for the mother. [ 17 ]  A review looking into this did not find enough good research to say whether or not nipple stimulation did reduce PPH. More research is needed to answer this question. [ 17 ]


Uterine massage is a simple first line treatment as it helps the uterus to contract to reduce bleeding. [ 18 ]  Although the evidence around the effectiveness of uterine massage is inconclusive, it is common practice after the delivery of the placenta. [ 18 ]


Intravenous or intramuscular  oxytocin  is the drug of choice for postpartum hemorrhage. [ 19 ] [ 20 ]   Ergotamine  may also be used. [ 2 ]


Oxytocin helps the uterus to contract quickly and the contractions to last longer. [ 21 ]  It is the first line treatment for PPH when its cause is the uterus not contracting well. [ 22 ]  A combination of syntocinon and  ergometrine  is commonly used as part of active management of the third stage of labour. [ 23 ]  This is called syntometrine. Syntocinon alone lowers the risk of PPH. [ 24 ]  Based on limited research available it is unclear whether syntocinon or syntometrine is most effective in preventing PPH but adverse effects are worse with syntometrine making syntocinon a more attractive option. [ 24 ]  Ergometrine also has to be kept cool and in a dark place so that it is safe to use. [ 25 ]  It may reduce the risk of PPH by improving the tone of the uterus when compared with no treatment, however it must be used with caution due to its effects of raising blood pressure and worsening pain. [ 25 ]  More research would be useful in determining the best doses of ergometrine [ 25 ]  and syntocinon. [ 23 ]


Oxytocin requires refrigeration, which may not always be available, particularly in low-resourced settings. [ 26 ]  When oxytocin is not available, misoprostol can be used. [ 22 ]  Misoprostol does not need to be kept at a certain temperature and research into its effectiveness in reducing blood loss appears promising when compared with a placebo in a setting where it is not appropriate to use oxytocin. [ 26 ]  Misoprostol can cause unpleasant side effects such as very high body temperatures and shivering. [ 27 ]  Lower doses of misoprostol appear to be safer and cause less side effects. [ 27 ]


Giving oxytocin in a solution of saline into the umbilical vein is a method of administering the drug directly to the placental bed and uterus. [ 28 ]  However quality of evidence around this technique is poor and it is not recommended for routine use in the management of the third stage. [ 28 ]  More research is needed to ascertain whether this is an effective way of administering uterotonic drugs. [ 28 ]  As a way of treating a retained placenta, this method is not harmful and has shown low certainty evidence of effectiveness. [ 29 ]


Carbetocin  compared with oxytocin produced a reduction in women who needed uterine massage and further uterotonic drugs for women having caesarean sections. [ 30 ]  There was no difference in rates of PPH in women having caesarean sections or women having vaginal deliveries when given carbetocin. [ 30 ]  Carbetocin appears to cause less adverse effects. More research is needed to find the cost effectiveness of using carbetocin. [ 30 ]


Tranexamic acid , a clot stabilizing medication, may also be used to reduce bleeding and blood transfusions in low-risk patients, [ 31 ]  however evidence as of 2015 was not strong. [ 2 ]  A 2017 trial found that it decreased the risk of death from bleeding from 1.9% to 1.5% in women with postpartum bleeding. [ 3 ]  The benefit was greater when the medication was given within three hours. [ 3 ]


In some countries, such as Japan,  methylergometrine  and other herbal remedies are given following the delivery of the placenta to prevent severe bleeding more than a day after the birth. However, there is not enough evidence to suggest that these methods are effective. [ 32 ]


Surgery may be used if medical management fails or in case of cervical lacerations, tears in the uterine wall or a uterine rupture. Methods used may include uterine artery ligation, ovarian artery ligation, internal iliac artery ligation, selective arterial embolization, B-lynch suture, and  hysterectomy . [ 33 ] [ 34 ] [ 35 ] [ 36 ]  Bleeding caused by traumatic causes should be managed by surgical repair. When there is bleeding due to uterine rupture a repair can be performed but most of the time a hysterectomy is needed. [ citation needed ]


There is currently no reliable evidence from randomised clinical trials about the effectiveness or risks of mechanical and surgical methods of treating postpartum bleeding. [ 37 ]


In those with  placenta accreta  (in which the placenta invades into the muscular layer of the uterus) planned caesarian delivery is recommended due to the very high risk of PPH although the optimal time for planned delivery is not well established with the  American College of Obstetricians and Gynecologists  recommending planned caesarian at delivery between 34 weeks and 35 weeks and 6 days gestation and the  Royal College of Obstetricians and Gynaecologists  recommending it between 35 and 36 weeks and 6 days. [ 7 ]  A hysterectomy is sometimes required, or planned, after the planned delivery. [ 7 ] [ 38 ]


The  World Health Organization  recommends the use of a device called the  non-pneumatic anti-shock garment  (NASG) for use in delivery activities outside of a hospital setting, the aim being to improve shock in a mother with  obstetrical bleeding  long enough to reach a hospital. [ 39 ]  External aortic compression devices (EACD) may also be used. [ 40 ] [ 41 ]


Uterine balloon tamponade  (UBT) can improve postpartum bleeding. [ 42 ]  Inflating a  Sengstaken–Blakemore tube  in the uterus successfully treats atonic postpartum hemorrhage refractory to medical management in approximately 80% of cases. [ 43 ]  Such procedure is relatively simple, inexpensive and has low surgical morbidity. [ 43 ]  A  Bakri balloon  is a balloon tamponade specifically constructed for uterine postpartum hemorrhage. [ 44 ]  While effective, commercially available devices may be expensive for settings in which postpartum hemorrhage is most common. Low-cost devices, such as the ESM-UBT, have been shown to be effective without the need for operative intervention. [ 45 ] [ 46 ] [ 47 ]  Uterine balloon tamponade devices may be left in place for up to 24 hours in the treatment of PPH. [ 7 ]


Uterine and vaginal packing are not recommended in the treatment of PPH and are associated with a high risk of infection. [ 7 ]


Protocols to manage postpartum bleeding are recommended to ensure the rapid giving of blood products when needed. [ 48 ]  A detailed stepwise management protocol has been introduced by the California Maternity Quality Care Collaborative. [ 49 ]  It describes four stages of obstetrical hemorrhage after childbirth and its application reduces maternal mortality. [ 50 ]


A  Cochrane review  suggests that active management (use of uterotonic drugs, cord clamping and controlled cord traction) during the third stage of labour may reduce severe bleeding and  anemia . [ 51 ]  However, the review also found that active management increased the patient's blood pressure, nausea, vomiting, and pain. In the active management group more patients returned to hospital with bleeding after discharge, and there was also a reduction in birthweight due to infants having a lower blood volume. The effects on the baby of early cord clamping was discussed in another review which found that delayed cord clamping improved iron stores longer term in the infants. [ 52 ]  Although they were more likely to need phototherapy (light therapy) to treat jaundice, the improved iron stores are expected to be worth increasing the practice of delayed cord clamping in healthy term babies. [ 52 ]


For preterm babies (babies born before 37 weeks) a review of the research found that delaying cord clamping may lead to fewer babies with bleeding in the brain, compared to early cord clamping. [ 53 ]


Another Cochrane review looking at the timing of the giving  oxytocin  as part of the active management found similar benefits with giving it before or after the expulsion of the placenta. [ 54 ]


There is no good quality evidence on how best to treat a secondary PPH (PPH occurring 24 hrs or more after the birth). [ 55 ]


Methods of measuring blood loss associated with childbirth vary, complicating comparison of prevalence rates. [ 56 ]  A systematic review reported the highest rates of PPH in Africa (27.5%), and the lowest in Oceania (7.2%), with an overall rate globally of 10.8%. [ 56 ]  The rate in both Europe and North America was around 13%. [ 56 ]  The rate is higher for multiple pregnancies (32.4% compared with 10.6% for singletons), and for first-time mothers (12.9% compared with 10.0% for women in subsequent pregnancies). [ 56 ]  The overall rate of severe PPH (>1000 ml) was much lower at an overall rate of 2.8%, again with the highest rate in Africa (5.1%). [ 56 ]


Prothrombin complex concentrate  ( PCC ), also known as  factor IX complex , sold under the brand name  Kcentra  among others, is a  combination medication  made up of  blood clotting factors   II ,  IX , and  X [ 9 ] (3-factor PCC) or, when also containing  factor VII  as does Kcentra, 4-factor PCC. [ 10 ]  It is used to treat and prevent bleeding in  hemophilia B  if pure factor IX is not available. [ 9 ] [ 11 ]  It may also be used for reversal of  warfarin  therapy. [ 11 ]  It is given by  slow injection into a vein . [ 9 ]  Another product, activated prothrombin complex concentrate or FEIBA (Factor Eight Inhibitor Bypassing Agent), may be used for acquired hemophilia. [ 12 ]


Common side effects include  allergic reactions , headache, vomiting, and sleepiness. [ 9 ] [ 13 ]  Other serious side effects include  blood clots  which may result in a  heart attack ,  stroke ,  pulmonary embolism , or  deep vein thrombosis . [ 13 ]   Antibodies  may form after long term use such that future doses are less effective. [ 11 ]


Prothrombin complex concentrate came into medical use in the 1960s. [ 14 ]  It is on the  World Health Organization's List of Essential Medicines . [ 15 ] [ 16 ]  It is made from  human plasma . [ 13 ]   Recombinant  factor IX is also available in a stand-alone preparation. [ 17 ]


Prothrombin complex concentrate reverses the effects of  warfarin  and other  vitamin K antagonist  anti-coagulants and is used in cases of significant bleeding in people with a  coagulopathy . It is also used when such a person must undergo an emergency operation. [ 18 ]  Other uses include a deficiency of one of the included clotting factors, either congenital or due to  liver disease , and  hemophilia . [ 18 ]  Several guidelines, including those from the  American College of Chest Physicians , recommend prothrombin complex concentrate for warfarin reversal in people with serious bleeding. [ 19 ] [ 20 ] [ 21 ] [ 22 ]


For rapid anticoagulation reversal for surgery, four-factor prothrombin complex concentrate reduces  international normalized ratio  (INR) and decreases bleeding during surgery when compared with administration of fresh frozen plasma. No differences in thromboembolic event was found. [ 23 ]


The package insert states that prothrombin complex concentrate is contraindicated in patients with  disseminated intravascular coagulation , a pathological activation of coagulation, [ 24 ]  because giving clotting factors would only further fuel this process. However, if the PCC is given because factor levels are low, it can restore normal coagulation. As PCC products contain  heparin , they are contraindicated in patients with  heparin-induced thrombocytopenia . [ 24 ]


Prothrombin complex concentrate contains a number of blood clotting factors. Typically this includes  factor II ,  IX , and  X . [ 9 ]  Some versions also contain  factor VII ,  protein C , and  protein S . [ 10 ] [ 24 ]   Heparin  may be added to stop early activation of the factors. [ 10 ]


The US  Food and Drug Administration  (FDA) announced its approval in 2013. [ 25 ]  The FDA approved Kcentra's orphan drug status in December 2012. [ 25 ] [ 26 ]


In the United States a dose of prothrombin complex concentrate costs about US $3200 [ 27 ]  though one study described the cost as $11 650. [ 28 ]  The Australian National Blood Authority sets Prothrombinex (500 IU) at around AUD$327.  [ 29 ]


A number of different formulations are available globally. [ 30 ]


The  Rh blood group system  is a  human blood group system . It contains proteins on the surface of red blood cells. After the  ABO blood group system , it is the most likely to be involved in transfusion reactions. The Rh blood group system consisted of 49 defined blood group  antigens [ 1 ]  in 2005. As of 2023, [update]  there are over 50 antigens among which the five antigens D, C, c, E, and e are among the most prominent. There is no d antigen. Rh(D) status of an individual is normally described with a  positive  (+) or  negative  (−) suffix after the  ABO  type (e.g., someone who is A+ has the A antigen and Rh(D) antigen, whereas someone who is A− has the A antigen but lacks the Rh(D) antigen). The terms  Rh factor ,  Rh positive , and  Rh negative  refer to the Rh(D) antigen only. Antibodies to Rh antigens can be involved in  hemolytic transfusion reactions  and antibodies to the Rh(D) and Rh antigens confer significant risk of  hemolytic disease of the newborn .


The Rh blood group system has two sets of nomenclatures: one developed by  Ronald Fisher  and  R. R. Race , the other by  Wiener . Both systems reflected alternative theories of inheritance. The Fisher–Race system, which is more commonly in use today, uses the CDE nomenclature. This system was based on the theory that a separate  gene  controls the product of each corresponding antigen (e.g., a "D gene" produces D antigen, and so on). However, the d gene was hypothetical, not actual.


The Wiener system used the Rh–Hr nomenclature. This system was based on the theory that there was one gene at a single locus on each of the two copies of chromosome 1, each contributing to production of multiple antigens. In this theory, a gene R 1  is supposed to give rise to the "blood factors" Rh 0 , rh′, and rh″ (corresponding to modern nomenclature of the D, C, and E antigens) and the gene r to produce hr′ and hr″ (corresponding to modern nomenclature of the c and e antigens). [ 3 ]


Notations of the two theories are used interchangeably in blood banking (e.g., Rho(D) meaning RhD positive). Wiener's notation is more complex and cumbersome for routine use. Because it is simpler to explain, the Fisher–Race theory has become more widely used. [ citation needed ]


DNA testing has shown that both are partially correct: There are in fact two linked genes, the  RHD  gene which produces a single immune specificity (anti-D) and the  RHCE  gene with multiple specificities (anti-C, anti-c, anti-E, anti-e). Thus, Wiener's postulate that a gene could have multiple specificities (something many did not give credence to originally) has been proved to be correct. On the other hand, Wiener's theory that there is only one gene has proved to be incorrect, as has the Fisher–Race theory that there are three genes, rather than the two. The CDE notation used in the Fisher–Race nomenclature is sometimes rearranged to DCE to more accurately represent the co-location of the C and E encoding on the RhCE gene, and to make interpretation easier. [ citation needed ]


The proteins which carry the Rh antigens are  transmembrane proteins , whose structure suggests that they are  ion channels . [ 4 ]  The main antigens are D, C, E, c and e, which are encoded by two adjacent gene loci, the  RHD  gene which encodes the RhD protein with the D antigen (and variants) [ 5 ]  and the  RHCE  gene which encodes the RhCE protein with the C, E, c and e antigens (and variants). [ 6 ]  There is no d antigen. Lowercase "d" indicates the absence of the D antigen (the gene is usually deleted or otherwise nonfunctional). [ citation needed ]


Rh  phenotypes  are readily identified through the presence or absence of the Rh surface antigens. As can be seen in the table below, most of the Rh phenotypes can be produced by several different Rh  genotypes . The exact genotype of any individual can only be identified by DNA analysis. Regarding patient treatment, only the phenotype is usually of any clinical significance to ensure a patient is not exposed to an antigen they are likely to develop antibodies against. A probable genotype may be speculated on, based upon the statistical distributions of genotypes in the patient's place of origin. [ citation needed ]


R 0  (cDe or Dce) is today most common in Africa. The allele was thus often assumed in early blood group analyses to have been typical of populations on the continent, particularly in areas below the Sahara. Ottensooser et al. (1963) suggested that high R 0  frequencies were likely characteristic of the ancient  Judean  Jews, who had emigrated from  Egypt  prior to their dispersal throughout the  Mediterranean Basin  and Europe [ 7 ]  on the basis of high R 0  percentages among  Sephardi  and  Ashkenazi   Jews  compared to native  European  populations and the relative genetic isolation of Ashkenazim. However, more recent studies have found R 0  frequencies as low as 24.3% among some  Afroasiatic -speaking groups in the Horn of Africa, [ 8 ]  as well as higher R 0  frequencies among certain other Afroasiatic speakers in  North Africa  (37.3%) [ 9 ]  and among some  Palestinians  in the  Levant  (30.4%). [ 10 ]  On the contrary, at a frequency of 47.2% of the population of Basque country having the lack of the D antigen, these people display the highest frequency of the Rh negative phenotype. [ 11 ]


• Figures taken from a study performed in 1948 on a sample of 2000 people in the United Kingdom. [ 12 ]


Rh antibodies are  Immunoglobulin G  (IgG) antibodies which are acquired through exposure to Rh-positive blood (generally either through pregnancy or transfusion of blood products). The D antigen is the most immunogenic of all the non-ABO antigens.  Approximately 80% of individuals who are D-negative and exposed to a single D-positive unit will produce an anti-D antibody. The percentage of alloimmunization is significantly reduced in patients who are actively  exsanguinating . [ 14 ]


All Rh antibodies  except  D display dosage (antibody reacts more strongly with red cells homozygous for an antigen than cells heterozygous for the antigen (EE stronger reaction vs Ee)).


If anti-E is detected, the presence of anti-c should be strongly suspected (due to combined genetic inheritance). It is therefore common to select c-negative and E-negative blood for transfusion patients who have an anti-E and lack the c antigen (in general, a patient will not produce antibodies against their own antigens). Anti-c is a common cause of delayed hemolytic transfusion reactions. [ 15 ]


The hemolytic condition occurs when there is an incompatibility between the blood types of the mother and fetus. There is also potential incompatibility if the mother is Rh negative, and the father is positive. When the mother conceives for the first time, with a positive child, she will become extremely sensitive. When any incompatibility is detected when she conceives the second time in less than two years then, the mother often receives an injection at 28 weeks' gestation and at birth to avoid the development of antibodies towards the fetus. If not given, then the baby will be dead and must be aborted. These terms do not indicate which specific antigen-antibody incompatibility is implicated. The disorder in the fetus due to Rh D incompatibility is known as  erythroblastosis fetalis .


When the condition is caused by the Rh D antigen-antibody incompatibility, it is called Rh D Hemolytic disease of the newborn or Rh disease. Here, sensitization to Rh D antigens (usually by feto-maternal transfusion during pregnancy) may lead to the production of maternal  IgG  anti-D antibodies which can pass through the  placenta . This is of particular importance to D negative females at or below childbearing age, because any subsequent pregnancy may be affected by the  Rh D hemolytic disease of the newborn  if the baby is D positive. The vast majority of  Rh disease  is preventable in modern  antenatal  care by injections of IgG anti-D antibodies ( Rho(D) Immune Globulin ). The incidence of Rh disease is mathematically related to the frequency of D negative individuals in a population, so Rh disease is rare in old-stock populations of Africa and the eastern half of Asia, and the Indigenous peoples of Oceania and the Americas, but more common in other genetic groups, most especially Western Europeans, but also other West Eurasians, and to a lesser degree, native Siberians, as well as those of mixed-race with a significant or dominant descent from those (e.g. the vast majority of Latin Americans and Central Asians).


Rh disease only occurs in human fetuses, however a similar disease called Neonatal isoerythrolysis (NI) can be observed in animal species of newborn horses, mules, pigs, cats, cattle, and dogs.  What differs between Rh disease and NI is the pathogenesis of hemolysis between human fetuses and the animal species.  With human mothers, the maternal antibodies are formed from the sensitization of foreign antigens of her unborn fetus’s red blood cells passing through the placenta causing hemolysis before birth. With other animals, however, these maternal antibodies are not passed through the placenta, but through  colostrum .  The newborn animal is without NI but soon develops hemolytic anemia after initial ingestion of its mother’s colostrum that contain antibodies that can be absorbed through the newborn’s intestines and are incompatible to its red blood cell antigen. After 48 hours of birth, the newborn may be allowed to nurse from its mother as her antibodies can no longer be absorbed through the neonate’s intestines.  Because the most active newborn animals consume the most colostrum, they may be the ones who are most affected by the blood incompatibility of antigen and antibody. [ 16 ]


According to a comprehensive study, the worldwide frequency of Rh-positive and Rh-negative blood types is approximately 94% and 6%, respectively. The same study concluded that the share of the population with Rh-negative blood type is set to fall further in the future primarily due to low population growth in  Europe . [ 17 ]  The frequency of Rh factor blood types and the RhD neg  allele  gene differs in various populations. [ citation needed ]


The D antigen is inherited as one gene ( RHD ) (on the short arm of the  first chromosome , p36.13–p34.3) with various alleles. Typically, Rhesus positive people have an intact RHD gene while negative people lack the gene (or have mutations in it). However, there are exceptions: for instance, Japanese and black Africans may have an intact gene that is not expressed or only at very low levels. [ 27 ]  The gene codes for the RhD  protein  on the red blood cell membrane. D− individuals who lack a functional  RHD  gene do not produce the D antigen and may be immunized by D+ blood. [ citation needed ]


The D antigen is a dominant trait. If both of a child's parents are  Rh negative,  the child will definitely be  Rh negative . Otherwise, the child may be  Rh positive  or  Rh negative,  depending on the parents' specific genotypes. [ 28 ]


The  epitopes  for the next 4 most common Rh antigens, C, c, E and e are expressed on the highly similar RhCE protein that is genetically encoded in the  RHCE  gene, also found on chromosome 1. It has been shown that the  RHD  gene arose by duplication of the  RHCE  gene during primate evolution. Mice have just one RH gene. [ 29 ]


The RHAG gene, which is responsible for encoding Rh-associated glycoprotein (RhAG), is found on chromosome 6a.


The polypeptides produced from the RHD and RHCE genes form a complex on the red blood cell membrane with the Rh-associated glycoprotein. [ 15 ]


On the basis of structural homology it has been proposed that the product of RHD gene, the RhD protein, is a  membrane transport protein  of uncertain specificity (CO 2  or NH 3 ) and unknown physiological role. [ 30 ] [ 31 ]  The three-dimensional structure of the related  RHCG  protein and biochemical analysis of the RhD protein complex indicates that the RhD protein is one of three subunits of an  ammonia transporter . [ 32 ] [ 33 ]  Three recent studies [ 34 ] [ 35 ] [ 36 ]  have reported a protective effect of the RhD-positive phenotype, especially RhD  heterozygosity , against the negative effect of latent  toxoplasmosis  on psychomotor performance in infected subjects. RhD-negative compared to RhD-positive subjects without  anamnestic  titres of anti- Toxoplasma  antibodies have shorter reaction times in tests of simple reaction times. And conversely, RhD-negative subjects with anamnestic titres (i.e. with latent toxoplasmosis) exhibited much longer reaction times than their RhD-positive counterparts. The published data suggested that only the protection of RhD-positive heterozygotes was long term in nature; the protection of RhD-positive  homozygotes  decreased with duration of the infection while the performance of RhD-negative homozygotes decreased immediately after the infection. The overall change in reaction times was always larger in the RhD-negative group than in the RhD-positive. [ citation needed ]


Rh-like proteins can be found even in species other than vertebrates (which have  red blood cells ) – worms, bacteria, and algae. All these Rh proteins have the same biochemical function of transporting CO 2 , differing slightly in their amino acid sequences. The Rh family as a whole is related to  ammonia transporters  (Amt). In  C. elegans  worms, disruption of the Rh1 gene causes growth defects under high CO 2  levels.  Chlamydomonas reinhardtii  algae fail to grow rapidly if its Rh gene is knocked down. Although  in vitro  evidence shows the Rh complex is capable of moving ammonia, its disruption does not cause growth defects under modified ammonia levels. [ 37 ] [ 38 ]


For a long time, the origin of RHD polymorphism was an evolutionary enigma. [ 39 ] [ 40 ] [ 41 ]  Before the advent of modern medicine, the carriers of the rarer allele (e.g. RhD-negative women in a population of RhD positives or RhD-positive men in a population of RhD negatives) were at a disadvantage as some of their children (RhD-positive children born to preimmunised RhD-negative mothers) were at a higher risk of fetal or newborn death or health impairment from hemolytic disease. [ 42 ]


Natural selection aside, the RHD-RHCE region is structurally predisposed to many mutations seen in humans, since the pair arose by gene duplication and remain similar enough for  unequal crossing over  to occur. [ 29 ]  In addition to the case where D is deleted, crossover can also produce a single gene mixing  exons  from both  RHD  and  RHCE , forming the majority of partial D types. [ 43 ] : 323


In serologic testing, D positive blood is easily identified. Units that are D negative are often retested to rule out a weaker reaction. This was previously referred to as D u , which has been replaced. [ 43 ] : 322   By definition, weak D phenotype is characterized by negative reaction with anti-D reagent at immediate spin (IS), negative reaction after 37 °C incubation, and positive reaction at anti-human globulin (AHG) phase. Weak D phenotype can occur in several ways. In some cases, this phenotype occurs because of an altered surface protein that is more common in people of European descent. An inheritable form also occurs, as a result of a weakened form of the R0 gene. Weak D may also occur as "C in trans", whereby a C gene is present on the opposite chromosome to a D gene (as in the combination R0r', or "Dce/dCe"). The testing is difficult, since using different anti-D reagents, especially the older polyclonal reagents, may give different results.


The practical implication of this is that people with this sub-phenotype will have a product labeled as "D positive" when donating blood. When receiving blood, they are sometimes typed as a "D negative", though this is the subject of some debate. Most "Weak D" patients can receive "D positive" blood without complications. [ 43 ] : 323   However, it is important to correctly identify the ones that have to be considered D+ or D−. This is important, since most blood banks have a limited supply of "D negative" blood and the correct transfusion is clinically relevant. In this respect,  genotyping of blood groups  has much simplified this detection of the various variants in the Rh blood group system.


It is important to differentiate weak D (due to a  quantitative  difference in the D antigen) from partial D (due to a  qualitative  difference in the D antigen). Simply put, the weak D phenotype is due to a reduced number of D antigens on a red blood cell. In contrast, the partial D phenotype is due to an alteration in D-epitopes. Thus, in partial D, the number of D antigens is not reduced but the protein structure is altered. These individuals, if alloimmunized to D, can produce an anti-D antibody. Therefore, partial D patients who are donating blood should be labeled as D-positive but, if receiving blood, they should be labeled as D-negative and receive D-negative units. [ 15 ]


In the past, partial D was called 'D mosaic' or 'D variant.' Different partial D phenotypes are defined by different D epitopes on the outer surface of the red blood cell membrane. More than 30 different partial D phenotypes have been described. [ 15 ]


Rh null  individuals have no Rh antigens (no Rh or RhAG) on their red blood cells. [ 44 ]  This rare condition [ 44 ]  has been called "Golden Blood". [ 45 ]  As a consequence of Rh antigen absence, Rh null  red blood cells also lack LW and Fy5 and show weak expression of S, s, and U antigens.


Red blood cells lacking Rh/RhAG proteins have structural abnormalities (such as  stomatocytosis ) and cell membrane defects that can result in  hemolytic anemia . [ 15 ] [ 44 ]


The first Rh null  blood was discovered in an  Aboriginal Australian  woman, in 1961. [ 46 ]  Only 43 individuals have been reported to have it worldwide. Only nine active donors have been reported. [ 45 ]  Its properties make it attractive in numerous medical applications, but scarcity makes it expensive to transport and acquire. [ 47 ]


As of 2023, over 50 antigens have been described in the Rh group system; among those described here, the D, C, c, E and e antigens are the most important. The others are much less frequently encountered or are rarely clinically significant. Each is given a number, though the highest assigned number (CEVF or RH61 according to the  ISBT  terminology) is not an accurate reflection of the antigens encountered since many (e.g. Rh38) have been combined, reassigned to other groups, or otherwise removed. [ 43 ] : 324


Some of the other Rh "antigens" are f ("ce", RH6), Ce (RH7), C w  (RH8), C x  (RH9), V (RH10), E w  (RH11), G (RH12), Tar (RH40), VS (RH20), D w  (RH23), and CE (RH22). Some of these groups, including f, Ce and CE, describe grouping of some existing groups. Others, like V, describe an  epitope  created by some other mutation on the  RHD  and  RHCE  genes. V in particular is caused by a mutation on  RHCE . [ 48 ]


The term "Rh" was originally an abbreviation of "Rhesus factor". It was discovered in 1939 by  Karl Landsteiner  and  Alexander S. Wiener , who, at the time, believed it to be a similar antigen found in  rhesus macaque  red blood cells. It was subsequently discovered that the human factor is not identical to the rhesus monkey factor, but by then, "Rhesus Group" and like terms were already in widespread, worldwide use. Thus, notwithstanding it is a misnomer, the term survives (e.g.,  rhesus blood group system  and the obsolete terms  rhesus factor ,   rhesus positive , and  rhesus negative  – all three of which actually refer specifically and  only  to the Rh D factor and are thus misleading when unmodified). Contemporary practice is to use "Rh" as a term of art instead of "Rhesus" (e.g., "Rh Group", "Rh factors", "Rh D", etc.).


The significance of their discovery was not immediately apparent and was only realized in 1940, after subsequent findings by  Philip Levine  and Rufus Stetson. [ 42 ]   The serum that led to the discovery was produced by immunizing rabbits with red blood cells from a  rhesus macaque . The antigen that induced this immunization was designated by them as  Rh factor  to indicate that  rhesus  blood had been used for the production of the serum. [ 49 ]


In 1939, Phillip Levine and Rufus Stetson published in a first case report the clinical consequences of non-recognized  Rh factor , hemolytic  transfusion reaction , and  hemolytic disease of the newborn  in its most severe form. [ 50 ]  It was recognized that the serum of the reported woman  agglutinated  with  red blood cells  of about 80% of the people although the then known blood groups, in particular  ABO  were matched. No name was given to this  agglutinin  when described. In 1940, Landsteiner and Wiener made the connection to their earlier discovery, reporting a serum that also reacted with about 85% of different human red blood cells. [ 51 ]


In 1941, Group O: a patient in  Irvington, New Jersey , US, delivered a normal [ clarification needed ]  infant in 1931; this pregnancy was followed by a long period of sterility. The second pregnancy (April, 1941) resulted in an infant with  icterus gravis . [ 52 ]  In May 1941, the third anti-Rh serum (M.S.) of Group O became available. [ 52 ]


Based on the serologic similarities, 'Rh factor' was later also used for antigens, and  anti-Rh  for antibodies, found in humans such as those previously described by Levine and Stetson. Although differences between these two sera were shown already in 1942 and clearly demonstrated in 1963, the already widely used term "Rh" was kept for the clinically described human antibodies which are different from the ones related to the rhesus monkey. This real factor found in  rhesus macaque  was classified in the  Landsteiner-Weiner antigen system  (antigen LW, antibody anti-LW) in honor of the discoverers. [ 53 ] [ 54 ]


It was recognized that the  Rh factor  was just one in a system of various antigens. Based on different models of genetic inheritance, two different terminologies were developed; both of them are still in use.


The clinical significance of this highly immunizing D antigen (i.e., Rh factor) was soon realized. Some keystones were to recognize its importance for blood transfusion (including reliable diagnostic tests), hemolytic disease of the newborn (including  exchange transfusion ), and very importantly the prevention of it by screening and  prophylaxis .


The discovery of  cell-free fetal DNA  in maternal circulation by Holzgrieve et al. led to the noninvasive genotyping of fetal Rh genes in many countries.


Rh deficiency syndrome  is a type of  hemolytic anemia  that involves  erythrocytes  whom membranes are deficient in  Rh antigens . It is considered a rare condition. [ 1 ]


Clinically, people with Rh deficiency show mild to moderate chronic  hemolytic anemia  with variable degrees of spherostomatocytosis. [ 2 ]


The condition is caused by silent alleles at the RH locus (amorph type) or suppressor genes unrelated to the locus (regulator type) that individuals inherit in an autosomal recessive manner. [ 3 ]


Vos originally described Rh-deficiency syndrome in 1961, when a sample of blood failed to respond with several Rh antisera. However, R. Ceppellini used the term "Rhnull" for the first time. So far, at least 43 people from 14 families have been reported in the literature as having the Rhnull phenotype. [ 4 ]


Rh-associated glycoprotein  ( RHAG ) is an  ammonia transporter   protein  that in humans is encoded by the  RHAG   gene . [ 5 ] [ 6 ]  RHAG has also recently been designated  CD241  ( cluster of differentiation  241). Mutations in the RHAG gene can cause  stomatocytosis . [ 7 ]


The  Rh blood group  antigens (MIM 111700) are associated with human erythrocyte membrane proteins of approximately 30 kD, the so-called Rh30 polypeptides. Heterogeneously glycosylated membrane proteins of 50 and 45 kD, the Rh50 glycoproteins, are coprecipitated with the Rh30 polypeptides on immunoprecipitation with anti-Rh-specific mono- and polyclonal antibodies. The Rh antigens appear to exist as a multisubunit complex of CD47 (MIM 601028), LW (MIM 111250), glycophorin B (MIM 111740), and play a critical role in the Rh50 glycoprotein [supplied by OMIM]. [ 6 ]


RHAG has been shown to  interact  with  ANK1 . [ 8 ]


Secretor status  refers to the presence or absence of water-soluble  ABO blood group antigens  in a person's  bodily fluids , such as  saliva ,  tears ,  breast milk ,  urine , and  semen . People who secrete these antigens in their bodily fluids are referred to as  secretors , while people who do not are termed  non-secretors . Secretor status is controlled by the  FUT2  gene (also called the  Se  gene), and the secretor  phenotype  is inherited in an  autosomal   dominant  manner, being expressed by individuals who have at least one functioning copy of the gene. The non-secretor phenotype ( se ) is a  recessive trait . [ 1 ] : 125–7   Approximately 80% of White people are secretors, while 20% are non-secretors. Non-secretors have reduced susceptibility to the most common strains of  norovirus . [ 2 ]  Expression of the antigens in the  Lewis blood group  is also affected by secretor status: non-secretors cannot produce the Le(b) antigen. [ 3 ] : 190


The expression of  ABO blood group antigens  is determined by the interaction of three genes: the  ABO gene , which controls expression of the A and B antigens; the  FUT1  or  H  gene, which controls expression of the  H antigen , the precursor of ABO antigens; and the secretor gene,  FUT2  or  Se . All of these genes encode  glycosyltransferases , which are  enzymes  that add  sugars  to precursor substances to create new substances. [ 1 ] : 123


The H antigen is required for ABO blood group antigens to be formed. [ note 1 ]  The  Se  gene, which encodes the enzyme α-2-L-fucosyltransferase, controls the formation of H antigen in bodily secretions. In people with the secretor genotype, the enzyme converts a precursor substance found in body fluids to the H antigen, which is then modified by the glycosyltransferases encoded by the ABO gene to produce the antigens corresponding to the person's ABO blood type. Because non-secretors cannot form H antigen in body fluids, they cannot express soluble ABO antigens. [ 1 ] : 124–6


Lewis blood group  phenotypes are controlled by the  FUT3  or  Le  gene and the  Se  gene. There are two major antigens in the Lewis system: Le(a) and Le(b). Individuals who are negative for  Le  express neither antigen and their blood type is designated as Le(a-b-). In individuals who are positive for  Le , the blood type is determined by the person's secretor status. The  Le  gene encodes a glycosyltransferase that produces the Le(a) antigen from a precursor substance. In secretors, α-2-L-fucosyltransferase modifies this precursor substance, which causes it to form Le(b) when acted on by the enzyme encoded by the  Le  gene. Thus, secretors who are positive for  Le  express the Le(a-b+) type, while non-secretors who are positive for  Le  express the Le(a+b-) blood type. [ note 2 ] [ 1 ] : 178–81  [ 3 ] : 196


Noroviruses  bind to secreted blood group antigens on the  mucosa  of the  digestive tract . [ 4 ] : 537   Because non-secretors do not express these antigens, they exhibit decreased susceptibility to most strains of the disease. [ 2 ]


Secretor status can be determined through genotyping or through  serologic  methods. In the serologic method, the person's saliva is boiled, then added to  reagents  containing  antibodies  against the A, B, and H antigens.  Red blood cells  expressing these antigens are then added to the saliva-reagent mixtures. If the person is a secretor, the antibodies will bind to the antigens in their saliva rather than the red blood cells, and will not cause red blood cells to  agglutinate . [ 5 ] : 25


Secretor status testing was historically used in  forensic science , but this has been made obsolete by advances in  DNA testing . [ 6 ] : 226


Approximately 80% of Caucasian people possess the  Se  gene and are secretors; the other 20% are non-secretors. [ 2 ]  The  frequency  of the  Se  gene is approximately 50% in most ethnic groups, but  Aboriginal Australians ,  Inuit , and some  Native American  and  Melanesian  groups exhibit a frequency of nearly 100%, while the frequency is only 22% in South India. [ 5 ] : 25


Selective immunoglobulin A (IgA) deficiency  ( SIgAD [ 1 ] ) is a kind of  immunodeficiency , a type of  hypogammaglobulinemia . People with this deficiency lack  immunoglobulin A  (IgA), a type of  antibody  that protects against infections of the mucous membranes lining the mouth, airways, and digestive tract. It is defined as an undetectable serum IgA level in the presence of normal serum levels of  IgG  and  IgM , in persons older than 4 years. It is the most common of the primary antibody deficiencies. Most such persons remain healthy throughout their lives and are never diagnosed.


85–90% of IgA-deficient individuals are asymptomatic, although the reason for lack of symptoms is relatively unknown and continues to be a topic of interest and controversy. [ 2 ]  Some patients with IgA deficiency have a tendency to develop recurrent sinopulmonary infections, gastrointestinal infections and disorders, allergies, autoimmune conditions, and malignancies. [ 2 ]  These infections are generally mild and would not usually lead to an in-depth workup except when unusually frequent. They rarely present with severe reactions, including  anaphylaxis , to  blood transfusions  or  intravenous immunoglobulin  due to the presence of IgA in these blood products.  Patients have an increased susceptibility to  pneumonia  and recurrent episodes of other  respiratory infections  and a higher risk of developing  autoimmune diseases  in middle age. [ 3 ]


IgA deficiency and  common variable immunodeficiency  (CVID) feature similar  B cell   differentiation  arrests, [ 4 ]  but it does not present the same  lymphocyte  subpopulation abnormalities. [ 5 ]  IgA-deficient patients may progress to  panhypogammaglobulinemia  characteristic of  CVID . [ 4 ]  Selective IgA and  CVID  are found in the same family. [ 4 ]


Selective IgA deficiency is inherited in less than half of cases, [ 6 ]  but has been associated with differences in  chromosomes   18 ,  14  and  6 . Selective IgA deficiency is often inherited, but fewer than half of all cases  but has been associated with some  congenital intrauterine infections . [ 4 ]


Pathogenesis of IgA Deficiency


‘In IgA-deficient patients, the common finding is a maturation defect in B cells to produce IgA’. ‘In IgA deficiency, B cells express IgA; however, they are of immature  phenotype  with the coexpression of IgM and IgD, and they cannot fully develop into IgA-secreting plasma cells’.  [ 7 ]


There is an inherited inability to produce  immunoglobulin A (IgA) , a part of the body's defenses against infection at the body's surfaces (mainly the surfaces of the respiratory and digestive systems).  As a result, bacteria at these locations are somewhat more able to cause disease. [ citation needed ]


Types include:


When suspected, the diagnosis can be confirmed by laboratory measurement of IgA level in the blood.  SIgAD is an IgA level < 7 mg/dL with normal IgG and IgM levels (reference range 70–400 mg/dL for adults; children somewhat less). [ 10 ]


The treatment consists of identification of co-morbid conditions, preventive measures to reduce the risk of infection, and prompt and effective treatment of infections. Infections in an IgA-deficient person are treated as usual (i.e., with antibiotics). There is no treatment for the underlying disorder. [ 11 ]  All SIgAD patients, even if asymptomatic, should receive pneumococcal and influenza vaccines, but should avoid live attenuated vaccines. [ 12 ]


There is a historical popularity in using  intravenous immunoglobulin  (IVIG) to treat SIgAD, but the consensus is that there is no evidence that IVIG treats this condition. [ 13 ] [ 14 ] [ 15 ]   In cases where a patient presents SIgAD and another condition which is treatable with IVIG, then a physician may treat the other condition with IVIG. [ 14 ]  The use of IVIG to treat SIgAD without first demonstrating an impairment of specific antibody formation is not recommended. [ 14 ] [ 16 ] [ 17 ] [ 15 ] [ 13 ]


Prognosis is excellent, although there is an association with  autoimmune disease .  Of note, selective IgA deficiency can complicate the diagnosis of one such condition,  celiac disease , as the deficiency masks the  high levels of certain IgA antibodies  usually seen in celiac disease. [ 18 ]


As opposed to the related condition  CVID , selective IgA deficiency is not associated with an increased risk of  cancer . [ 19 ]


Patients with Selective IgA deficiency rarely have severe reactions to blood transfusions. [ 20 ]  Although Selective IgA deficiency is common, [ 21 ] [ 22 ] [ 23 ]  severe reactions to blood transfusions are very rare. [ 20 ] [ 22 ] [ 24 ]   People with selective IgA deficiency do not require special blood products unless they have a history of a severe allergic reaction to a blood transfusion. [ 25 ] [ 26 ] [ 27 ]


Prevalence varies by population, but is on the order of 1 in 100 to 1 in 1000 people, [ 21 ]  making it relatively common. SIgAD occurs in 1 in 39 to 1 in 57 people with celiac disease. This is much higher than the prevalence of selective IgA deficiency in the general population. [ 28 ]  It is also significantly more common in those with type 1  diabetes . [ citation needed ]


It is more common in males than in females. [ 29 ]


EDAR  ( EDAR hypohidrotic ectodermal dysplasia )


ENSG00000138623 ENSG00000288455


NM_003612 NM_001146029 NM_001146030


NP_001139501 NP_001139502 NP_003603


Semaphorin 7A, GPI membrane anchor  ( John Milton Hagen blood group ) ( SEMA7A ) also known as  CD108  ( C luster of  D ifferentiation 108), is a human  gene . [ 5 ]


SEMA7A is a membrane-bound  semaphorin  that associates with cell surfaces via a glycosylphosphatidylinositol (GPI) linkage. SEMA7A is also known as the John-Milton-Hagen (JMH) blood group antigen, an 80-kD glycoprotein expressed on activated  lymphocytes  and  erythrocytes .[supplied by OMIM] [ 5 ]  SEMA7A is expressed in various adult tissues such as adipose, colon, esophagus, heart, brain, spleen, testis, lung, ovary, and uterus. [ 6 ]


SEMA7A promotes axonal growth and is involved in  mesoderm  derived somite formation. Murine embryonic Sema7A expression is highest on day 7, which is indicative of its role on the differentiation of germ layer structure. [ 7 ]  Embryonic Sema7A expression is noticeable at all developmental stages as well as in the newborn and adult thymus, indicative of a development T-cell role. [ 7 ]  In wild type neurons, addition of Sema7A under  in vitro  conditions promotes elongation and branching in a dose dependent manner. [ 8 ]  Unlike the majority of semaphorins, SEMA7A enhances axonal growth and is imperative for proper embryonic axonal tract formation. [ 9 ]  Limited expression of SEMA7A is found in the hindbrain as opposed to an abundance of SEMA7A expression found in both the cranial and trunk neural crest cells, which indicates an involvement in migration and differentiation. [ 10 ]  Sema7A -/- mice show defects in olfactory tract development. [ 11 ]


In normal breast tissue, mRNA expression of SEMA7A is low or not expressed, but activation to re-express SEMA7A occurs in these adult tissues to cause pleiotropic effects which increase tumorigenesis. [ 12 ] [ 13 ]  Tumor cell growth, EMT, lung metastasis and angiogenesis have been linked to increased Sema7a expression in murine models. [ 14 ] [ 15 ] [ 16 ]  Increased SEMA7A expression correlates with poor prognosis in breast cancer patients. [ 13 ]  Tumors increase SEMA7A expression in an involuting environment, but knockout of SEMA7a in mouse models undergoing involution decreases lymphangiogenesis. [ 17 ]


This protein is known to have eight variants in the extracellular region: seven lie within the Sema domain and one within the PSI domain. [ citation needed ]


This protein forms dimers. [ citation needed ]


This protein acts as a receptor for the malaria parasite  Plasmodium falciparum .


Serious Hazards of Transfusion (SHOT)  is the  United Kingdom 's haemovigilance scheme.


It collects and analyses anonymized information on  adverse events  and  blood transfusion  reactions. When SHOT has identified risks related to transfusion, it produces recommendations within its annual reports to improve  patient safety . These reports are freely available on its website.


SHOT, together with the  Medicines and Healthcare products Regulatory Agency (MHRA) , works to support haemovigilance reporting in the UK.


SHOT's statistical data has been used to decrease  bacterial infections  through better skin cleansing procedures and the incidence of life-threatening  transfusion-related acute lung injury  (TRALI) in the UK, by discouraging the use of  fresh frozen plasma  from female donors. [ 1 ]  The cause of TRALI is not fully understood, and may have more than one mechanism, [ 2 ]  but most cases are associated with transfusion of plasma or other blood products that contain some  antibodies  that the donor developed during  pregnancy . [ 3 ] [ 4 ]   Not using plasma donation from female donors for transfusions eliminates the risk of exposing the recipient to pregnancy-related antibodies, and therefore reduces the risk of TRALI. [ 4 ]   The collected information has also provided evidence to support the pre-existing practice of leukodepletion (depleting the number of  leukocytes , or white blood cells, from the product) to reduce the risk of transfusion-associated  graft-versus-host disease  and  post-transfusion purpura  in immunocompromised patients. [ 1 ]


SHOT's data has also focused attention on  human errors , with the result that staff training and procedures have been improved.  For example, SHOT's data demonstrated that increasing the use of wristbands for patient identification and portable, bedside  barcode readers  reduced the risk of an error caused by  human factors . [ 1 ]


SHOT was established in 1996. [ 5 ]   During the first ten years, it collected more than 2,000 confidential reports about  transfusion safety  problems or  near misses . [ 5 ]   During the first two years of voluntary reports, about half of these errors involved giving the wrong  type of blood  or blood component to a patient. [ 6 ]   This happens, for example, if hospital staff accidentally take the wrong item out of the blood bank refrigerator. [ 6 ]   Less than 1% of errors resulted in an infection. [ 6 ]


By 2012, almost all NHS hospitals, trusts, and health boards had registered with SHOT and were submitting reports. [ 1 ]   Participation is now mandatory. [ 1 ]


The "Better Blood Transfusion" strategy by the UK's Department of Health was based on evidence collected by SHOT. [ 5 ]


Solvent detergent plasma  is a form of  blood plasma  made from plasma collected from many people which is then processed with  solvents  as a form of  virus processing , to try to get rid of  viruses . [ 1 ]


Stem cell   fat grafting  is the  autotransplantation  of adipose-derived stem cells (ADSCs) extracted from fat-abundant donor sites (e.g. thigh or stomach) to other areas such as the face, breast, and hip to reconstruct the operative areas into desirable shapes. [ 1 ]  ADSCs are  multipotent   stem cells  found in adipose tissues, displaying similar  differentiation  potentials to bone marrow-derived  mesenchymal stem cells  (BM-MSCs). [ 2 ]


The discovery of ADSCs brought advances to the field of regenerative medicine and aesthetic procedures. While the use of embryonic stem cells was reconsidered for ethical reasons, ADSCs were noticed by plastic surgeons for their characteristics such as  pluripotent   differentiation  potential,  paracrine  activities,  immunomodulatory  functions, and homing effect. [ 3 ]


Regardless of the numerous benefits, there are few side effects and  oncology  safety issues. The rising investment in stem cell cosmetic therapy reflects high expectation and demands, especially in South Korea.  Further research on the effectiveness of ADSCs grafting proposed that the aftermath of the therapy can be affected by the quality of stem cells and diet by fostering adequate conditions for stem cell growth and sufficient consumption of nutrients. [ 4 ]


James Thomson  at the University of Wisconsin first isolated human  embryonic stem cells  in 1998. However, due to the ethical controversies regarding embryonic stem cells,  induced pluripotent stem cells  (iPSCs) were proposed as a substitute. The remaining oncological concern of iPSCs was eased by suggesting  adult stem cells  as the most primary resource of  regenerative medicine . [ 5 ]


The first isolation of mesenchymal stem cells from the bone marrow was done by Friednstein  et al.  in 1986 and considered as a primary clinical stem cell source. However, the painful acquisition and low cell yield limited further research. Zuk  et al.  later isolated ADSCs and found them to have the same potential as BM-MSCs. Although later other stem cells were identified from different parts of the human body, ADSCs were considered to be the safest as it was the easiest stem cell to isolate and did not require cell expansion, and so they are still used as a primary source of fat transfer therapies. [ 6 ]


The concept of autologous fat grafting was first suggested in 1893. The first report described that the adipose tissue without changing its structure was implanted to the adherent scars from  osteomyelitis . The result was successful and soon widely used in different fields of aesthetic procedures such as breast augmentation and  rhinoplasties . [ 6 ]


In 1978, a  liposuction  procedure was invented to remove the excessive fat depositions. Later, Illouz found that this procedure is the ideal supplier of fat tissue and used impurified lipoaspirate as a transplant in 1983 and Fournier proposed a reinjection technique of aspirated fat. [ 6 ]


The third period started in 1994 when S.R. Coleman introduced the Coleman technique, which uses adipose tissue for lipid cell transfer. The lipoaspirate was centrifuged to separate the  stromal vascular fraction  (SVF), including ADSCs, from blood, tissue, fluid, and lipids, [ 3 ]  though the fat cell retention rate varied from 30% to 95%. The first theory that explains graft survival is the Cell Survival Theory, which suggests that the transfer of viable adipocytes for adequate circulation enhances the survival rate and this can be done by developing the processing and injection techniques to minimize trauma. [ 6 ]


Host replacement theory suggests that the retention rate after fat grafting is determined by the ADSCs replacing adipocytes, as the successful ADSC activation and replacement of adipocytes is related to the early death of transferred adipocytes in ischemic conditions. [ 6 ]


Fang  et al.  proposed that ADSCs are the most widely used due to their  pluripotent   differentiation  potentials,  paracrine activity  and  immunomodulatory  function. ADSCs are one type of  mesenchymal stem cells  (MSCs), and they exhibit high similarities with BM-MSCs, [ 7 ]  and they are capable of multilineage differentiation into fats,  cartilages ,  cardiac muscles ,  nerves , skins, and  Skeletal muscles . They also tend to survive for a longer period with a higher proliferative capacity than other stem cells. ADSCs secret pro- angiogenic  factors and anti- apoptotic  factors like  cytokines ,  chemokines ,  growth factors ,  mRNAs , and  microRNAs . Then, they act on different systems where they were transplanted and regenerate cells in these transplanted systems. Moreover, as ADSCs resemble BM-MSCs, they have  immunosuppressive  characteristics that inhibit both innate and adaptive immune systems. However, their capacity is even stronger than BM-MSCs by secretion of immunosuppressive factors such as  IL-6  and  TGF-B . Additionally, they perform as immune tolerators to suppress lymphocyte proliferation; such a property suggests the possibility of ADSCs being used for  xenotransplantation . [ 8 ]


The homing effect refers to the engraftment of ADSCs to bone marrow  endothelium  due to the arrest of ADSCs within the  vasculature  of a tissue. ADSCs are engrafted to the bone marrow endothelium;  adhesion  interactions are activated to the bone marrow endothelium. Thus, such engraftment increases the probability of long-term survival of transferred fats. The homing effect follows three main processes: rolling, adhesion, and transmigration. During the rolling, ADSCs migrate and interacts with vascular endothelial cells in bone marrow in shear-resistant and low-affinity manners. As ADSCs adhere to bone marrow endothelium, MSCs express several different molecules that increase the adhesion such as  CD44 isoforms  and  integrins . As ADSCs transmigrate through vessels in bone marrow, interaction and signaling between stromal-derived chemokine factor -1 ( SDF-1 ) and receptor  CXCR4  is the most crucial process. [ 9 ] [ 10 ]


Mechanical and enzymatic (ME) methods are the most common isolation methods, although there is no standard method. [ 11 ]  Accordingly, Glass and Ferretti proposed one of the ME methods which is to apply tumescent-assisted liposuction using a mechanical or ultrasound-assisted  liposuction cannula . Through liposuction, the fat sample is digested by enzymatic activities of  collagenase  or  trypsin  in  Dulbecco’s modified Eagle's medium  (DMEM). The resultant tissue suspension undergoes incubation and agitation at around 37 °C and is filtered through a strainer to remove unnecessary  debris . The cell pallet left after  centrifugation  is the SVF, which is seeded on the plate after the second suspension with bovine calf serum, 1%  penicillin  or  streptomycin , and  L-glutamine . The adherent properties of ADSCs on the plate allow for their isolation, [ 12 ]  but due to the inconvenience of isolating the pure ADSCs, a cell-assisted lipo-transfer (CAL) is more commonly used. CAL transforms poor ADSCs into enriched ADSCs by mixing SVF isolate and aspirated fat. [ 13 ]  The efficacy of CAL was proven by the increased survival rate of autologous breast augmentation when introduced around 270 ml for each breast. [ 14 ]


Around 1.5 million women have breast implant surgeries per year, [ 15 ]  but the side effects can be severe and cause irreversible damage to the patient's body. The most well-known side effects are foreign body sensation,  calcification , fat cell  necrosis , capsular construction, rupture,  cysts  and some fat cells leaving the implanted area.


In most cases, calcification and cysts are the biggest threat of breast augmentation surgery. Fat stem cells that fail to pick up a new blood supply will die and be removed from the body by immune cells. However, if they are missed, the cluster will lead to calcification and cyst formation. These are visible on the breast as lump sometimes and are more dangerous when these dead cells are detected as cancer cells, which hinders an accurate diagnosis of  breast cancer . The calcified tissue will be diagnosed as a benign cancer and not cause any harm. However, if the tissue is severely damaged the entire breast needs to be removed. Once a patient is diagnosed with breast implant calcification, regular mammograms should be done to monitor the possible cancer development. [ 16 ]


Gornitsky  et al.  from McGill University conducted a  systematic review  of 4,577 patients who have received the facial fat transfer. The most prevalent side effects reported were  asymmetry , skin irregularities,  hypertrophy , prolonged  edema , and fat  necrosis . [ 17 ]


The homing effect may have advantages in increasing the long-term survival of transferred fat, but concerns remain for patients with post-oncologic history, specifically breast cancer. It is more alarming since breast tumors are closely located with adipose tissue, as they develop a favorable  microenvironment  for cancer progression through homing and migration. [ 18 ]  There are cancer-associated  adipocytes  (CAAs) crucial for  metastasis  and the progression of tumors. Under normal conditions, the adipocytes are mature and they do not differentiate. However, when ADSCs migrate and circulate in blood vessels by the homing effect, it can result in the progression of tumor growth. Furthermore, the properties of migratory cells also promote tumor growth by secretion of trophic factors such as  adipokines  like  FGF ,  ILs  and  IGF-binding proteins ; this increases  vascularisation  as such oncogenic properties are unusual for other BM-MSCs or lung-derived MSDCs. [ 19 ]


The stem cell market has grown largely along with the increasing awareness of stem cells in regenerative medicine. The Google web search big data analysis showed that the terms  stem cell  facelift  and  stem cell breast augmentation  had 197,000 and 302,000 outcomes, respectively, according to the American Society of Plastic Surgeons. [ 20 ]


With the rising interest in stem cell cosmetic therapy, the adjacent figure demonstrates the content analysis on the 50 clinical websites that appeared on  Google  for “stem cell therapy”, “treatment” or “stem cell facelift” in November 2013. The result showed that 90% of the clinics use autologous adult stem cells, 71% of clinics obtained stem cells from patient fat, 90% of procedures delivered cells through subcutaneous methods, and facial anti-ageing treatment was advertised the most in stem cell treatments as well as stem cell breast augmentation therapies. [ 21 ]


The International Association of Aesthetic Plastic Surgery announced the Korean plastic surgery market is estimated to be worth about $440 million as of 2017. It is a quarter of the world market, and the number of plastic surgeries per year ranked first (13.5 per 1,000 people per year). Korean stem cell markets formed a scale of $1.1 billion in 2016 and they are expected to grow to 26.67% annually by 2025 ($9.5 billion). [ 22 ] [ 23 ]


In 2017 the government invested in the bio sector for the highest proportion for new drug development (13%), and only 4% on stem cells ($112 million). CartistemTM, Inc. Medipost published successfully developed stem cell-based degenerative knee cartilage therapy and has achieved more than 10 billion sales since 2017. [ 22 ]


Behind the large stem cell cosmetic therapy market size of South Korea, non-specialists  practice without a license  in some clinics. According to the  National Statistical Office , the number of plastic surgeons was 1,924 in 2018, and the Korean Plastic Surgery Association estimates that non-specialists in cosmetic surgery will be about 10 times that of specialists.


Dr. Shin mentioned, "There have been similar surgeries that advocate stem cell breast plastic surgery recently. When receiving stem cell breast surgery, patients need to check whether the doctor has officially proved and whether the hospital has stem cell researchers and high-quality equipment." [ 24 ]


Studies have shown that diet is closely related to stem cell proliferation and performance. Among numerous chemicals that affect the entire stem cell differentiation and settlement process, it is shown that taking extra supplements such as below can help stem cells to function better.


The word "syngenic" or "syngeneic" (from the Greek word for a relative) means genetically identical, or sufficiently identical and immunologically compatible as to allow for transplantation. For example, it may be used for something transplanted from an  identical twin . When the cells are collected from the same patient on whom they will be used, a graft is called  autologous .  Syngeneic  refers to a graft transferred between genetically identical animals or people. [ 1 ]  A syngeneic graft is known as an  isograft . [ 2 ]


Related terms include: [ citation needed ]


Tranexamic acid  is a medication used to treat or prevent excessive  blood loss  from  major trauma ,  postpartum bleeding , surgery,  tooth removal ,  nosebleeds , and  heavy menstruation . [ 6 ] [ 7 ]  It is also used for  hereditary angioedema . [ 6 ] [ 2 ]  It is taken either  by mouth ,  injection into a vein , [ 6 ]  or by intramuscular injection.