Tacrolimus

Tacrolimus (also FK-506 or fujimycin, trade names Prograf, Advagraf, Protopic) is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection.

It is also used in a topical preparation in the treatment of atopic dermatitis (eczema), severe refractory uveitis after bone marrow transplants, exacerbations of minimal change disease, and the skin condition vitiligo.

It is a 23-membered macrolide lactone discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis.
It reduces interleukin-2 (IL-2) production by T-cells. Mechanism of action Tacrolimus is chemically known as a macrolide. In T-cells, activation of the T-cell receptor normally increases intracellular calcium, which acts via calmodulin to activate calcineurin. Calcineurin then dephosphorylates the transcription factor NF-AT (nuclear factor of activated T-cells), which moves to the nucleus of the T-cell and increases the activity of genes coding for IL-2 and related cytokines. Tacrolimus prevents the dephosphorylation of NF-AT. In detail, Tacrolimus reduces peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP12 (FK506 binding protein) creating a new complex. This FKBP12-FK506 complex interacts with and inhibits calcineurin thus inhibiting both T-lymphocyte signal transduction and IL-2 transcription.

Gene Rh D

Rh blood group, D antigen also known as Rh polypeptide 1 (RhPI) or cluster of differentiation 240D (CD240D) is a protein that in humans is encoded by the RHD gene.

The RHD gene codes for the RhD erythrocyte membrane protein that is the Rh factor antigen of the Rh blood group system.
RHD has sequence similarity to RHCE, RhAG, RhBG, and RhCG and these five genes constitute the Rh family. It was proposed that the erythrocyte Rh complex is a heterotrimer of RhAG, RhD, and RhCE protein subunits.
RhAG is a functional ammonia transporter and is required for normal cell surface expression of RhD and
RhCE.

Patients who lack RhD/RhCE/RhAG on the surface of their erythrocytes have hemolytic anemia.

Antibodies to the RhD protein can cause Rh disease.

Teste de Coombs

The Direct Coombs test is used to test for autoimmune hemolytic anemia; i.e., a condition of a low count of red blood cells (aka RBCs) caused by immune system lysis or breaking of RBC membranes causing RBC destruction.

In certain diseases or conditions an individual's blood may contain IgG antibodies that can specifically bind to antigens on the RBC surface membrane, and their circulating RBCs can become coated with IgG alloantibodies and/or IgG autoantibodies. Complement proteins may subsequently bind to the bound antibodies and cause RBC destruction.

The direct Coombs test is used to detect these antibodies or complement proteins that are bound to the surface of red blood cells; a blood sample is taken and the RBCs are washed (removing the patient's own plasma) and then incubated with antihuman globulin (also known as "Coombs reagent"). If this produces agglutination of RBCs, the direct Coombs test is positive, a visual indication that antibodies (and/or complement proteins) are bound to the surface of red blood cells.

The indirect Coombs test is used in prenatal testing of pregnant women, and in testing blood prior to a blood transfusion. It detects antibodies against RBCs that are present unbound in the patient's serum. In this case, serum is extracted from the blood sample taken from the patient. Then, the serum is incubated with RBCs of known antigenicity; that is, RBCs with known reference values from other patient blood samples. If agglutination occurs, the indirect Coombs test is positive.

IgG

Intravenous immunoglobulin (IVIG) is a blood product administered intravenously. It contains the pooled, polyvalent, IgG (immunoglobulin (antibody) G) extracted from the plasma of over one thousand blood donors. IVIG's effects last between 2 weeks and 3 months. It is mainly used as treatment in three major categories:

• Immune deficiencies such as X-linked agammaglobulinemia, hypogammaglobulinemia (primary immune deficiencies), and acquired compromised immunity conditions (secondary immune deficiencies) featuring low antibody levels.
• Autoimmune diseases, e.g. immune thrombocytopenia, and inflammatory diseases, e.g. Kawasaki disease.
• Acute infections.

IVIG use[edit source | editbeta]

IVIG is given as a plasma protein replacement therapy (IgG) for immune deficient patients who have decreased or abolished antibody production capabilities. In these immune deficient patients, IVIG is administered to maintain adequate antibody levels to prevent infections and confers a passive immunity. Treatment is given every 3–4 weeks. In the case of patients with autoimmune disease, IVIG is administered at a high dose (generally 1-2 grams IVIG per kg body weight) to attempt to decrease the severity of the autoimmune diseases such as dermatomyositis. Currently, IVIg is being increasingly used off-label in a number of pathological conditions; the increasing world-wide usage of IVIg may lead to shortages of this beneficial drug.

IVIG is useful in some acute infection cases such as pediatric HIV infection as well as autoimmune, such as Guillain–Barré syndrome.^[1]

As asthma treatment[edit source | editbeta]

Asthma is a condition which can have many causes. In patients with both immune abnormalities and an infection causing asthma, the triggering infection could be eliminated with IVIG therapy.^[2] However, most asthma patients have a normal immune system and their asthma is the result of lower airway inflammation which can be managed in the context of a healthy immune system.^[2][3] Despite popularity of use, IVIG is not recommended for recurrent asthma infections unless the patient presents an impaired response to vaccine immunizations or natural infections.^[2][3]

Mechanism of action[edit source | editbeta]

The precise mechanism by which IVIG suppresses harmful inflammation has not been definitively established but is believed to involve the inhibitory Fc receptor.^[4][5] However, the actual primary target(s) of IVIG in autoimmune disease are still unclear. IVIG may work via a multi-step model where the injected IVIG first forms a type of immune complex in the patient.^[6] Once these immune complexes are formed, they interact with activating Fc receptors on dendritic cells^[7] which then mediate anti-inflammatory effects helping to reduce the severity of the autoimmune disease or inflammatory state.

Additionally, the donor antibody may bind directly with the abnormal host antibody, stimulating its removal. Alternatively, the massive quantity of antibody may stimulate the host's complement system, leading to enhanced removal of all antibodies, including the harmful ones. IVIG also blocks the antibody receptors on immune cells (macrophages), leading to decreased damage by these cells, or regulation of macrophage phagocytosis.

IVIG may also regulate the immune response by reacting with a number of membrane receptors on T cells, B cells, and monocytes that are pertinent to autoreactivity and induction of tolerance to self.^[8]

A recent report stated that IVIG application to activated T cells leads to their decreased ability to engage microglia. As a result of IVIG treatment of T cells, the findings showed reduced levels of tumor necrosis factor-alpha and interleukin-10 in T cell-microglia co-culture. The results add to the understanding of how IVIG may affect inflammation of the central nervous system in autoimmune inflammatory diseases.^[9]

IVIG notes[edit source | editbeta]

• IVIG is an infusion of IgG antibodies only. Therefore, peripheral tissues that are defended mainly by IgA antibodies, such as the eyes, lungs, gut and urinary tract are not fully protected by the IVIG treatment.
• X-linked agammaglobulinemia patients are immune to the most dangerous adverse effect, anaphylactic shock, as they do not have the antibodies to react against the treatment. Anaphylactic shock has a higher chance to occur in IgA deficient patients which do have other antibody types.
• In case of recurring side effects, it is recommended to slow the pace of the IVIG administration and to reduce the dosage. It is also advisable to change IVIG brand, as some people react against a specific brand.
• If the patient is diabetic, he should take into consideration the medium in which the antibodies are solubilized in the IVIG treatment, as some brand solubilize antibodies with high concentrated sugars(such as sucrose and maltose).
• U.S. Food and Drug Administration (FDA) guidelines for IVIG state the product should be:
  • Prepared out of at least 1,000 different human donors.
  • All four IgG subgroups (1-4) should be present.
  • The IgG should maintain biological activity and lifetime of at least 21 days.
  • Does not contain samples which are HIV, hepatitis B, hepatitis C positive.
  • Screened and treated in a manner that destroys viruses.
• IVIG is also considered a modulator of the immune system and was shown to be beneficial in treating numerous autoimmune diseases such as relapsing, myasthenia gravis, pemphigus, polymyositis(PM), dermatomyositis (DM), Wegener's granulomatosis (WG), Churg-Strauss syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP) and more.
• IVIG can be given to pregnant women.
• IVIG is also used as a treatment for unexplained recurring miscarriages. The effectiveness of the therapy is controversial.
• IVIG cost is stable but over $75/g. ($15,000 for a 100 kg (220 lbs) person at 2g/kg)

IVIG dose[edit source | editbeta]

Dosage of IVIG is dependent on indication.

For primary immune dysfunction 100 to 400 mg/kg of body weight every 3 to 4 weeks is implemented. However that is just a starting dose. The dose needs to be adjusted on the needs of the patient. The therapeutic dose is the one that prevents serious infections and prevents the patient from getting more infections than the general population.

For neurological and autoimmune diseases 2 grams per kilogram of body weight is implemented for three to six months over a five day course once a month. Then maintenance therapy of 100 to 400 mg/kg of body weight every 3 to 4 weeks follows.

FDA-approved indications[edit source | editbeta]

• Allogeneic bone marrow transplant
• Chronic lymphocytic leukemia
• Common variable immunodeficiency (CVID) a group of approximately 150 primary immunodeficiencies (PIDs), which have a common set of features (including hypogammaglobulinemia) but which have different underlying causes
• Idiopathic thrombocytopenic purpura
• Pediatric HIV
• Primary immunodeficiencies
• Kawasaki disease
• Chronic inflammatory demyelinating polyneuropathy (CIDP). Only the "Gamunex" brand manufactured by Talecris is approved for CIDP (in 2008), under the U.S. Orphan Drug law provisions
• Kidney transplant with a high antibody recipient or with an ABO incompatible donor

In 2004 the FDA approved the Cedars-Sinai IVIG Protocol which has been 90-95% successful in removing antibodies from the blood of kidney transplant recipients so that they can accept a living donor kidney from any healthy donor no matter blood type (ABO incompatible) or tissue match.

Sistema reticuloendotelial

Sistema reticuloendotelial (SRE) ou sistema mononuclear fagocitário é o sistema orgânico constituído por células que, situadas em diferentes locais do organismo, têm características reticulares e endoteliais e são dotadas de capacidade fagocitária, intervindo, desse modo, na formação de células sanguíneas, no metabolismo do ferro, além de desempenharem funções de defesa contra infecções generalizadas.

São os monócitos e todas as células a que eles dão origem em outros tecidos como os macrófagos, as células micróglias e as células de Kupffer, por exemplo, que compõem tal sistema. Consiste nas células fagocitárias localizadas em tecidos conjuntivos reticulares - Este é um tipo de tecido conjuntivo formado por fibras reticulares feitas de colagénio tipo III (não são exclusivas deste tecido, mas só neste é que são predominantes). As fibras reticulares são formadas por fibroblastos especiais chamados células reticulares. 

O tecido reticular encontra-se no: Fígado, Baço, nódulos linfaticos e medula óssea.

Haptoglobina

A haptoglobina é uma proteína do plasma sangüíneo. Ela forma um complexo com a Hemoglobina, quebrando-a em globina e grupo heme. O grupo heme, por sua sua vez, dissocia-se em bilirrubina e ferro livre, este que vai ser reutilizado na síntese de novas hemácias.

Os níveis de haptoglobina aumentam em resposta a diversas situações: estresse orgânico, infecção, inflamação aguda ou necrose tecidual.

Seus níveis caem após um processo hemolítico, porque os complexos com Hemoglobina são rapidamente retirados do plasma pelo sistema reticuloendotelial. Pode ocorrer queda da haptoglobina também em doenças hepáticas. A haptoglobina não se liga à mioglobina. Por isso, usa-se como diagnóstico diferencial para a rabdomiólise: se os níveis de haptoglobina estiverem normais, a mioglobina foi responsável pelo excesso de grupos heme no sangue ou na urina. Assim, confirma-se o diagnóstico de rabdomiólise.

Blister cell

A degmacyte (aka "bite cell") is an abnormally shaped red blood cell with one or more semicircular portions removed from the cell margin. These "bites" result from the removal of denatured hemoglobin by macrophages in the spleen.

Glucose-6-phosphate dehydrogenase deficiency, in which uncontrolled oxidative stress causes hemoglobin to denature and form Heinz bodies, is a common disorder that leads to the formation of bite cells. The "bites" in degmacytes are smaller than the missing red blood cell fragments seen in schistocytes. The hemoglobin is concentrated on one side of the cell while the other, resembling a blister, is colourless.

Bernard–Soulier syndrome

Bernard–Soulier syndrome (BSS), also called hemorrhagiparous thrombocytic dystrophy,^[1] is a rare autosomal recessive coagulopathy (bleeding disorder) that causes a deficiency of glycoprotein Ib (GpIb), the receptor for von Willebrand factor, which is important in clot formation.

The incidence is estimated to be less than 1 in 1 million persons, based on cases reported from Europe, North America, and Japan.^[2]

It is a Giant Platelet Syndrome that is characterized by abnormally large platelets.

Symptoms[edit source | editbeta]

As with other congenital platelet function defects, BSS often presents as a bleeding disorder with symptoms^[3] of:

• Perioperative and postoperative bleeding
• Bleeding gums
• Easy bruising
• Heavy menstrual periods
• Epistaxis
• Abnormally prolonged bleeding from small injuries

Characteristics[edit source | editbeta]

Characterized by prolonged bleeding time, thrombocytopenia, increased megakaryocytes (bone marrow platelet progenitors), and decreased platelet survival, Bernard–Soulier syndrome is associated with quantitative or qualitative defects of the platelet glycopotein complex GPIb/V/IX. The degree of thrombocytopenia may be estimated incorrectly, due to the possibility that when the platelet count is performed with automatic counters, giant platelets (which may be as frequent as 70–80% in occasional patients) may reach the size of red blood cells and, as a consequence, are not recognized as platelets by the counters. BSS platelets do not aggregate to ristocetin, and this defect is not corrected by the addition of normal plasma, distinguishing it from von Willebrand disease. The platelet responses to physiologic agonists is normal, with the exception of low concentrations of thrombin. Bleeding events, which may be very severe, can be controlled by platelet transfusion. Most heterozygotes, with few exceptions, do not have a bleeding diathesis.

It presents as a bleeding disorder due to the inability of platelets to bind and aggregate at sites of vascular endothelial injury.^[4]

Emperipolesis

In medicine, emperipolesis is the presence of an intact cell within the cytoplasm of another cell.

It is derived from Greek (em is inside, peri is around, polemai is wander about). It is related to peripolesis, which is the attachment of one cell to another.

Hemophagocytic syndrome

Hemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic syndrome,^[1] is an uncommon hematologic disorder that, typically, clinically manifests as fever, hepatosplenomegaly, lymphadenopathy, jaundice and rash, with laboratory findings of histiocytosis,^[2] and the pathologic finding ofhemophagocytosis. Pancytopenia (anemia, neutropenia, and thrombocytopenia), markedly elevated serum ferritin levels, and abnormal liver enzymes are frequently present.

HELLP syndrome

HELLP syndrome is a life-threatening obstetric complication usually considered to be a variant or complication of pre-eclampsia.^[1] Both conditions usually occur during the later stages of pregnancy, or sometimes after childbirth. "HELLP" is an abbreviation of the three main features of the syndrome:^[2]

• Hemolysis
• Elevated Liver enzymes
• Low Platelet count

Signs and symptoms[edit source | editbeta]

HELLP usually begins during the third trimester; rare cases have been reported as early as 21 weeks gestation. Often, a patient who develops HELLP syndrome has already been followed up for pregnancy-induced hypertension (gestational hypertension), or is suspected to develop pre-eclampsia (high blood pressure and proteinuria). Up to 8% of all cases present after delivery.

Women with HELLP syndrome often "do not look very sick."^[3] Early symptoms can include:

• In 90% of cases, either epigastric pain described as "heartburn" or right upper quadrant pain.^[3][4]
• In 90% of cases, malaise.^[4]
• In 50% of cases, nausea or vomiting.^[4]

There can be gradual but marked onset of headaches (30%), blurred vision, and paresthesia (tingling in the extremities). Edema may occur but its absence does not exclude HELLP syndrome. Arterial hypertension is a diagnostic requirement, but may be mild. Rupture of the liver capsule and a resultant hematoma may occur. If the patient has a seizure or coma, the condition has progressed into full-blowneclampsia.

Disseminated intravascular coagulation is also seen in about 20% of all women with HELLP syndrome,^[5] and in 84% when HELLP is complicated by acute renal failure.^[6] Pulmonary edema is found in 6% of all women with HELLP syndrome,^[5] and in 44% when HELLP is complicated by acute renal failure.^[6]

Patients who present with symptoms of HELLP can be misdiagnosed in the early stages, increasing the risk of liver failure and morbidity.^[7] Rarely, post caesarean patients may present in shock condition mimicking either pulmonary embolism or reactionary haemorrhage.

Pathophysiology[edit source | editbeta]

The exact cause of HELLP is unknown, but general activation of the coagulation cascade is considered the main underlying problem. Fibrin forms crosslinked networks in the small blood vessels. This leads to a microangiopathic hemolytic anemia: the mesh causes destruction of red blood cells as if they were being forced through a strainer. Additionally, platelets are consumed. As the liver appears to be the main site of this process, downstream liver cells suffer ischemia, leading to periportal necrosis. Other organs can be similarly affected. HELLP syndrome leads to a variant form of disseminated intravascular coagulation (DIC), leading to paradoxical bleeding, which can make emergency surgery a challenge.

An association has been demonstrated between long chain 3-hydroxyacyl-CoA-dehydrogenase (LCHAD) deficiency and maternal HELLP and AFLP (acute fatty liver of pregnancy). This inherited, autosomal recessive abnormality of fatty-acid oxidation can result in significant morbidity and mortality in infants, if untreated. Treatment with dietary manipulation is possible. Approximately 80% of infants with LCHADhave been born after pregnancies complicated by AFLP or HELLP. However, what is not known is how many pregnancies complicated by AFLP or HELLP result in infants with LCHAD deficiency.^[8]

ad hoc

Ad hoc is a Latin phrase meaning "for this".

It generally signifies a solution designed for a specific problem or task, non-generalizable, and not intended to be able to be adapted to other purposes (compare a priori). Common examples are organizations, committees, and commissions created at the national or international level for a specific task.

Haplotype

A haplotype (from the Greek: ἁπλοῦς, haploûs, "onefold, single, simple") in genetics is a combination of alleles (DNA sequences) at adjacent locations (loci) on a chromosome that are inherited together. A haplotype may be one locus, several loci, or an entire chromosome depending on the number of recombination events that have occurred between a given set of loci.