Final Exam - Diseases

Thrombocytopenia

1. Decreased production due to infections or sepsis, nutrient deficiencies 2. Peripheral destruction of platelets by antibodies 3. Sequestration of platelets in the spleen (portal hypertension or splenomegaly) 4. Dilution of blood from fluid infusion or transfusion Tend to bleed but it is from small venules and capillaries instead of large vessels as in hemophilia. Petechiae (small red or purple blotches) Labs 1. ↓ platelet count •Failure of the clot to retract could be a sign of thrombocytopenia b/c of how much the platelets normally contribute to this process.

HIV/AIDS pathogenesis

1. Selective affinity of HIV for certain human cells- HIV is cytotoxic → depletion esp. in T-lymphocytes (but also, monocytes,) is typical in AIDS 2. Effects of the virus on the immune system- Initial infection stimulates B-cells to produce antibodies, which appear in circulation within weeks. - Most infected enter a latent phase and are asymptomatic. Virus continues to replicate and destroys more helper T-lymphocytes Death = overwhelming infection or tumor like B-cell Non-Hodgkin's Lymphoma or Kaposi Sarcoma

Antiphospholipid Antibody Syndrome cause

1. Thromboembolic events (arterial and venous) in any organ system, the most common venous event is deep leg vein thrombosis, the most common arterial event is stroke 2. Pregnancy-related complications (miscarriage, stillbirth, placental infarctions, preterm delivery, or severe pre-eclampsia.) 3. Thrombocytopenia 4. Commonly seen in conjunction with other autoimmune diseases, such as lupus (SLE).

Hyper-IgM syndrome

1. X-linked: defective CD40L signaling •Required stimulation for class switching via CD40 from CD40L on follicular helper T cells not received •Signal required for full activation of macrophages not received. 2. non-X-linked: defective AID •Protein responsible for isotype switching (activation-induced cytidine deaminase (AID)) cannot target switch regions between heavy chain isotype regions to mediate class switching •Impaired isotype switching by B cells in both types results in high levels of low affinity IgM in circulation •Little/no IgG or IgA "Classroom setting where a student is seated in an X-shaped chair, eating M&M's and then wants to go to a different class, but can't. The student then got too hyper and dropped a CD of the top 40 Long songs." Pathogenesis: Due to the mutated CD40L (on helper T cells) or CD40 receptor (on B-cells), we cannot get a 2nd signal that is normally delivered to helper T-cells during B-cell activation and class switch. Consequently, cytokines (IL-4 and IL-5) necessary for immunoglobulin class switching are not produced (stays as IgM) This results in low IgA, IgG, and IgE → recurrent pyogenic infections due to poor opsonization, especially at mucosal sites •Severe pyogenic infections early in life (b/c low levels of opsonizing antibodies) •Opportunistic infection w/ PNEUMOCYTIS (methenamine silver staining as disc-shaped cysts with central spores), CRYPTOSPORIDIUM Labs: High levels of IgM and low levels of IgG, IgA, IgE. Tx: IVIG, prophylactic abx, stem cell transplantation

Disseminated intravascular coagulation (DIC) labs

1. ↓ platelet count (platelets are used to form thrombi) 2. ↑ PT/PTT/TT (increased time to clot - good indicator of bleed) 3. ↓ fibrinogen (used up to make thrombi) 4. MAHA - some RBC sheared by thrombi (schistocytes) 5. Elevated D-dimer (elevated fibrin split products) (best screening test) (Derived from splitting of CROSS-LINKED FIBRIN, not fibrinogen) How to distinguish between this and generalized factor deficiency INHIBITOR MIXING STUDY. - PTT does NOT correct upon mixing normal plasma with patient's plasma due to an inhibitor (there is a blocking problem - so much Abs against factor 8 that the Abs will even bind the incoming normal plasma that has factor 8 → no correction) - PTT DOES correct in a deficiency problem because there is just a deficiency, not a blocking problem. (correction seen as we provided supplement)

DiGeorge Syndrome immunological problem

22q11.2 deletion which leads to a developmental abnormality = 3rd and 4th pharyngeal pouches don't form properly •Numerous and variable congenital defects = heart defects, abnormal facial features, absent parathyroids, cleft palate, thymic hypoplasia, developmental delays and learning difficulties, seizures, neurobehavioral problems •Reduced or absent T cells (George has a small head and low nasal bridge. He does math: 22/11 = 2, no 3 and 4 = no Thymus = effect heart = no PTH and Ca) George wants to play "Catch-22" = Cardiac Abnormalities, Abnormal facies, Thymic aplasia, Cleft palate, Hypocalcemia. Deletion of 11.2 on chromosome 22.

NEMO deficiency

A subunit of IKK, a kB kinase inhibitor, is defective. Complete absence of NEMO activity = not compatible with life "NEMO and the shark (conical teeth, thick skin, and fish don't sweat cuz they are in water, and they don't have hair b/c scales) (no inflammation b/c in water - no burning in water). (IKK = organization that shark is in)" Pathogenesis: Since IKK is defective, NF-kB therefore cannot activate and remains bound to I-kB and unable to initiate transcription for proteins that establish a state of inflammation. This affects both innate and adaptive immune response. NF-kB from being activating → prevents transcription of innate and adaptive genes for inflammation. → ↓ production of cytokines, adhesion molecules, and other molecules for inflammation. Clinical: Increased susceptibility to mycobacterial infections, and a range of pyogenic infections (Pneumococcus and Staphylococcus most common) Ectodermal dysplasia (ED): patients will have thick skin, conical teeth, absence of sweat glands and thin/sparse hair. Dry flaky skin for ectodermal dysplasia Infections found everywhere - lung, skin, CNS, liver, abdomen, urinary tract, bones, GI tract Complete absence of NEMO activity is incompatible with life. Genetics: X-Linked recessive disorder Epidemiology: Almost always in boys Therapy: preventing infection and complication from infection

Antiphospholipid Antibody Syndrome

ACQUIRED thrombophilia A disorder of coagulation that causes blood clots in arteries and veins due to autoantibodies directed against numerous negatively charged phospholipids (constituents of cell membranes) in the body, especially antibodies against Cardiolipin, Apolipoprotein H (beta-2 glycoprotein I), and the lupus anticoagulant.

Development of lupus anticoagulant

ACQUIRED thrombophilia •An immunoglobulin that binds to phospholipids and proteins associated with the cell membranes. •This antibody may interfere with blood clotting, but paradoxically, may also cause thrombosis. •Accounts for frequent occurrence of arterial thrombosis and is the most common of the acquired blood protein defects. •Most patients with a lupus anticoagulant do not have SLE, and only a small proportion will proceed to develop it. Also, pt's with SLE are more likely to develop a lupus anticoagulant. •It is important to remember, that the term anticoagulant describes its function in-vitro, that results in prolongation of the PTT, due to phospholipid inhibition. •**In VIVO, paradoxically, it functions as a coagulant, its hypercoagulability probably due to platelet activation, accounting for the arterial thrombosis and habitual abortions (repeated miscarriages)

SCID subtype- Adenosine Deaminase Def (ADA)

ADA or purine nucleoside phosphorylase (PNP) mutation leads to ADA deficiency → increased dATP, prevent DNA synthesis, lymphocytes unable to proliferate, and eventual absence of T, B and NL lymphocytes ADA is necessary to deaminate adenosine and deoxyadenosine for excretion as waste productions. Adenosine and deoxyadenosine are toxic to lymphocytes. No ADA= lymphotoxicity Underdeveloped Thymus = few T cells Genetics = Auto Recessive (AR) 2nd most common form of SCID

Paroxysmal nocturnal hemoglobinuria

Absent glycosylphosphatidylinositol (GPI) linked proteins → Decay accelerating factor (DAF or CD55) and CD59 (protectin) defects/absence → rendering cells susceptible to destruction by complement. Stages: 1. RBCs coexist with complement. 2. DAF (decay accelerating factor) and MIRL (membrane inhibitor of reactive lysis) and CD59 are on the surface of RBC to protect against complement-mediated damage 3. DAF and MIRL and CD59 are secured by GPI. 4. Without GPI = no more DAF or CD59 = complement- mediated damage = RBC lysed Paroxysmal nocturnal = "on some nights" -When we sleep, we breathe shallowly → retain CO2 → respiratory acidosis → activate complements (damage if we don't have GPI) CD59 = prevents formation of MAC DAF = inhibits formation of classical or alternative C3 convertase Normocytic anemia: Intravascular hemolysis = hemoglobinemia and hemoglobinuria (dark urine in the morning); hemosiderinuria seen days after hemolysis. Main cause of death = THROMBOSIS of hepatic, portal, or cerebral veins (due to destroyed platelets releasing cytoplasmic contents into circulation) Complications:- Iron deficiency anemia (chronic loss of Hb in urine) - Acute leukemia (AML) (10% pts) Progression to pancytopenia/aplastic anemia Labs: Sucrose test = screen for disease by activating complement Acidified serum test = confirmatory test by activating complement Flow cytometry = detect lack of CD55 (DAF) on blood cells. Negative Coombs test. Decreased haptoglobin Tx: Complement inhibition with anti-C5 antibody

Coagulation Factor Inhibitor

Acquired antibody against a coagulation factor resulting in impaired factor function - anti-FVIII most common Clinical and lab findings similar to hemophilia How to distinguish between this and hemophilia A: MIXING STUDY. - PTT does NOT correct upon mixing normal plasma with patient's plasma due to an inhibitor (there is a blocking problem - so much Abs against factor 8 that the Abs will even bind the incoming normal plasma that has factor 8 → no correction) - PTT DOES correct in hemophilia A because there is just a deficiency, not a blocking problem.

Immune Thrombocytopenic Purpura (ITP)

Acute form = weeks after a viral infection or immunization Chronic form = primary or secondary -Primary ITP = acquired ITP due to autoimmune mech leading to platelet destruction and underproduction -Secondary ITP = associated with another condition (HIV, Hep C, SLE, CLL) Acute form = CHILDREN Chronic form = ADULTS, usually women of childbearing ages 20-40. Pathogenesis: Autoimmune production of IgG against platelet antigens (e.g., GPIIb/IIIa = no fibrinogen linking) Most autoantibodies are produced by plasma cells in the spleen. Antibody-bound platelets are consumed by splenic macrophages, resulting in thrombocytopenia. *PARADOX = the problem is made the spleen and the spleen is what cleans it up and causes the body to overall lose platelets. Clinical: Acute form = self-limited, usually resolving within weeks of presentation -Fever, rash, and/or constitutional symptoms Chronic form = may cause short-lived thrombocytopenia in offspring since antiplatelet IgG can cross the placenta -Petechiae, easy bruising, epistaxis, gum bleeding, and hemorrhages after minor trauma. -Serious intracerebral or subarachnoid hemorrhages are uncommon. ***HIV virus = contains protein sequences homologous to GPIIIa → when infected, there will be production of antibodies specific for GPIIIa, which reacts against the platelet antigens → platelet fragmentation and thrombocytopenia. Labs: 1. ↓ platelet count, often <50 K/uL 2. Normal PT/PTT (coagulation factors NOT affected) 3. ↑ Megakaryocytes in bone marrow biopsy (bone marrow trying to compensate loss of platelets by making more) 4. Normal platelet morphology (this is a quantitative disorder) Treatment: Antibodies directed against GIIb/IIIa or Ib/IX complexes can be detected in 80% of chronic cases. 1. IVIG = intravenous immunoglobulin = Idea is having the splenic macrophages eat these incoming Ig instead of the ones bound to platelets (overrun the spleen with this) Used to raise platelet count in symptomatic bleeding Short-lived because once the drug 'runs out', the problem of splenic eating comes out. 2. Splenectomy = eliminates the primary source of antibody and site of platelet destruction (performed in refractory cases) *Suspect if CHILD WITH THROMBOCYTOPENIA AND PETECHIAE FOLLOWING A VIRAL ILLNESS. *Suspect if patient is bleeding, has petechiae, and thrombocytopenia with normal platelet morphology - CHECK FOR SECONDARY CAUSE *to distinguish from TTP = TTP has the extra MAHA (schistocytes) and decreased renal function!!

Disseminated intravascular coagulation (DIC) causes

Almost always secondary to another disease process: 1. Obstetric complications (tissue thromboplastin in amniotic fluid activates coagulation) 2. Sepsis (esp. E. coli and N. meningitidis) - Endotoxins from the bacterial wall and cytokines (e.g., TNF and IL-1) induce endothelial cells to make tissue factor 3. Adenocarcinoma - mucin activates coagulation 4. Acute promyelocytic leukemia - primary granules activate coagulation 5. Rattlesnake bite - venom activates coagulation 6. Others - post-op STOP Making New Thrombi -Sepsis -Trauma -Obstetrics -Pancreatitis (acute) -Malignancy -Nephrotic -Transfusion

Aspirin

Aspirin irreversibly inactivates cyclooxygenase → lack of TXA2 impairs aggregation. Prescribed for stroke prevention b/c it limits platelet aggregation by inhibiting formation of thromboxane A2 which activates platelets, attract platelets to the site of injury, and is a vasoconstrictor.

Marasmus

Attributed primarily to a shortage of calories (carbohydrates, protein, fat) -Metabolic adjustment to starvation -Can't make enough ATP Protective up to 12 months (Babies can sustain on nutrients from mother due to breastfeeding, but once the mother stops or lacks nutrients, then the baby will lack carbohydrates, micronutrients, and macronutrients → disease) Chronic diseases: cancer, anorexia nervosa **Absence of edema Emaciation (old face) Wasting of subcutaneous tissue, muscle, and fat Weak and lethargic Lack of appetite Anemia Creatine <60% Creatine is found in meat Very little "Meat" in Marasmus

Kwashiorkor

Attributed primarily to shortage of protein Described as failed metabolic adjustment to starvation >18 months (1st to 2nd child) 1st baby avoided Marasmus due to breastfeeding but once the 2nd child comes along and mother begins to breastfeed the 2nd child and stop the 1st child, the 1st child will most likely consume a lot of rice (a lot of carbohydrates, but not a lot of protein) Seen in SE Asia. Acute condition: trauma, sepsis **Presence of edema Hepatomegaly (distended abdomen) Normal weight Alert, hungry Patchy dark and pale skin Serum albumin <2.8 g/dL Blood protein made by liver but if the liver is having trouble, serum albumin is low

Protein C deficiency

Autosomal Dominant -Genetic trait that predisposes to thrombosis -Most of the mutations that cause protein C deficiency change single protein building blocks (amino acids) in protein C, which disrupts its ability to control blood clotting Prevalence is estimated to be between 0.3-0.5% of the general population, and is associated with an increased risk of venous thrombosis. 1:500 prevalence 20-75% penetrance Venous thrombosis by age 40 Pathogenesis: Protein C is activated when cleaved by thrombin bound to thrombomodulin on the endothelial cell surface o Activated PC (APC) inactivates clotting factors Va and VIIIa, thus downregulating the clotting cascade -Without protein C = can't inactivate the activated 5 and 8 → more clots. -Decreases negative feedback for coagulation factors Clinical: **detected by warfarin reaction ⇒ warfarin skin necrosis - Normally, the initial stage of warfarin therapy results in a temporary deficiency of C and S (shorter half-life) relative to 2, 7, 9, and 10. Note that there is a buffer before C and S runs out and when it does, we are going to get temporary thrombosis (but minor in which we can't see to the naked eye) - In protein C and S deficiency, upon giving warfarin, we are going to get a much quicker onset of thrombosis, which is seen on the skin. - This is why warfarin starts as a combo therapy with Heparin or DOAC until the rest of the factors 2, 7, 9, and 10 are destroyed. •Can either be low production (those heterozygous for the mutation), which are the majority of pt's. •Those homozygous for the mutation have life-threatening neonatal thrombosis with purpura fulminans 50% reduction in PC → clotting cascade can't be turned off •Clinical diagnosis through PC functional assay (w/o coumadin tx) •Large number of genetic changes renders genetic testing mostly useless. DO NOT GIVE WARFARIN

Antithrombin III deficiency

Autosomal dominant disorder characterized by venous thrombosis or PE -Mutations to AT3 cause AT3 deficiency (antithrombin deficiency) -Variable penetrance (50% asymptomatic) •Can also be acquired, in nephrotic syndrome causing renal failure, antithrombin is lost in the urine, leading to higher activity of Prothrombin with an increased tendency for thrombosis. Recurrent thrombotic episodes by age 40. More commonly associated with trauma, surgery, pregnancy, and contraceptive use Pathogenesis: •Antithrombin III is a glycoprotein produced by the liver and released into the plasma which inactivates thrombin. Antithrombin III (AT3) inhibits serine proteases (blood coagulation proteases) - Inhibits factors IX, X, XI, and XII (9, 10, 11, 12 - intrinsic pathway) and thrombin (II). - Heparin like molecules (HLM) or Heparin activates/potentiates ATIII⇒ Deactivates thrombin and coagulation factors Decreases protective effect of HLM produced by endothelium ⇒ thrombosis (clotting) risk No HLM means high coag factors 50% reduction in AT activity → increased risk of thrombosis. (need at least 70% for normal functional level and ensure effective inhibition of blood coagulation proteases) Deep leg vein and mesenteric vein thrombosis are common, arterial thrombosis rare. Labs: PTT unchanged with normal heparin dose Clinical diagnosis through AT3 functional assay oNo change in PT, PTT, under-responsive to heparin Tx: Must give high dose Heparin to activate the limited ATIII and then add Coumadin (Warfarin) **NIGHT DOSE

Immune complex disease clinical

Buildup of immune complexes → neutrophil activation → extensive tissue damage. Susceptibility to pyogenic infections. Most severe immune complex disease = C1 or C4 defects

Hereditary Angioedema (HAE)

C1 inhibitor (C1INH) defect → complement regulatory protein defect → Hereditary angioedema (HAE) Autosomal DOMINANT disorder. C1 (C1q + 2C1r + 2C1s) is found in the classical pathway and the C1INH normally causes C1r and C1s to dissociate from C1. C1INH defect = control of the classical complement pathway and clotting cascade to be affected → C2a, bradykinin (vasoactive peptides) to accumulate → fluid leakage from blood into tissue. (want controlled deposition - if no inhibitor, we going to get excess cuts and excess C2a) ***Subepithelial swelling: face, extremities, larynx, abdomen Other conditions due to C1INH defect: PNH, HUS Can't give ACE-1 (contraindication b/c it is a vasodilator)

Immune complex disease immunology problem

C1, C2, C4 deficiency → impaired C3b and C4b formation → immune complexes

Immune complex disease pathogenesis

C1, C2, and C4 are key in the classical pathway. C1 would normally cut C2 and C4 to make C2aC4b, which would be C3 convertase. C3 convertase would convert C3 into C3b. C3b binds to pathogen surfaces and acts as an opsonin for phagocytosis by macrophages via CR1 receptor. Because there is a C1, C4 deficiency (also C2), there will be a problem with C3b and C4b → prevent binding of CR1 on erythrocytes, which is supposed to be transported to spleen and liver for removal by local macrophages. Leads to buildup of immune complexes containing antigen complement and antibodies that can induce neutrophil activation and extensive tissue damage.

C3 defect

C3 defect → impaired formation of C3b → impaired opsonization and some does lead to immune complex disease (minor) C3 is converted into C3a and C3b by C3 convertase. If C3 is impaired, then C3b deposition will be impaired, which will impair opsonization. (decreased phagocytosis by macrophages) Susceptibility to infections (esp. Pyogenic bacteria)

C5-C9 defect

C5-C9 defect → impaired complement mediated lysis because of problems to the terminal membrane attack complex (MAC) C5 is converted to C5a and C5b by C5 convertase in the alternative pathway. C5b complexes with C6-C9 to make the MAC. If there is any problem from C5-C9, the MAC complex can't form. MAC's main job is to lyse microbes by making a whole in the cell membrane. **Susceptibility to Neisseria (gram -) (encapsulated bacteria)

Ca2+ removal (prevent clotting process)

Ca2+ ions can be limited to prevent the clotting process. Negatively charged citrate ion can neutralize the Ca2+ Also, oxalate compound can be used to bind Ca2+ into calcium oxalate Citrate is safer b/c the liver can remove it from the blood. Oxalate can be toxic to the body. *Ca2+ = required for all blood clotting reactions (except for first 2 steps of the intrinsic pathway)

X-linked agammaglobulinemia (XLA)

Complete lack of immunoglobulin due to disordered B-cell maturation. Pre- and pro-B cells cannot mature (i.e, naive B cells can't become plasma cells) Due to mutated Bruton tyrosine kinase (BTK), a signaling molecule that normally signals B-cells to become plasma cells. The lack of BTK signaling protein during B cell development prevents B cells from entering pre-B cell stage of development. Since there is no mature B-cells, we get NO immunoglobulins (Ig) or antibodies to fight against infections → recurrent infections "XLA = BTK" "Bruton = Brutal defects in B cell makes little Boys feel unwell" Clinical: •Recurrent infections •6 months of age when maternal antibodies are depleted which can lead to bacterial (H. flu, Strep pneumo, Staph Aureus) or viral (enterovirus) infections. •Need antibodies for opsonization of bacteria •Violaceous and inflammatory ulcer of pyoderma gangrenosum "PNEUMONIA, OTITIS MEDIA, HYPOPLASIA OF TONSIL AND OTHER LYMPHOID TISSUE" Genetics: BTK mutation; X-linked recessive Epidemiology: Almost always Males and babies Labs: •B cells absent/decreased in circulation •All classes of immunoglobulins depressed •Germinal center of lymph nodes, Peyer's patches, Appendix, and Tonsils underdeveloped •Plasma cells absent •T-cell mediated reactions normal Tx: No live vaccines. Treat with polled sera IVIG **Low levels of mature B cells (which express CD19, CD20, and CD21) in addition to recurrent episodes of respiratory and gastrointestinal tract infections when a child is older than 6 months (when the maternal IgG has decreased) are highly suggestive of X-linked (Bruton) agammaglobulinemia.

Hemophilia A and B clinical

Deep tissue, joint, and postsurgical bleeding. Bleeding after trauma but variability (ex: some patients bleed for several days after tooth extraction) •**Hemarthroses, most commonly in ankles, knees and elbows. Painful swelling and reduced mobility (BLOOD IN JOINTS = 'swelling in joint' = HEMOPHILIA) •Repeat bleeds into a target joint lead to complete immobility and muscle wasting •Prone to excessive soft tissue and mucocutaneous bleeds •Intracranial bleeding develops rarely, however is the leading cause of death of neonates and lifetime risk is 2%-8% •Muscle bleeds: calf, thigh, buttocks, and forearm •Increased risk of post-operative or post-traumatic hemorrhage, and bleeding into joints can lead to arthritis. Onset is in early childhood; often mild disease is first noticed as bleeding gums. •Symptoms in B less severe than hemophilia A •B is generally less severe than A due to most mutations in B being hypomorphic, while most in A are null. •Hypomorphic describes a mutation that causes a partial loss of gene function. A hypomorph is a reduction in gene function through reduced (protein, RNA) expression or reduced functional performance, but not a complete loss. NOSEBLEED + MULTIPLE BRUISES + HEMARTHROSIS = HEMOPHILIA

Wiskott-Aldrich syndrome (WAS)

Defective CYTOSKELETON function due to mutation in WASP gene (BAD ACTIN FILAMENT ASSEMBLY) Defective reorganization of cytoskeleton prevents T cells from delivering cytokines, signaling to B-cells, macrophages, and other target cells Also, difficult for child's bone marrow to produce platelets → bleeding less severe than SCID. First signs: petechiae and bruising Spontaneous nose bleeds and bloody diarrhea Eczema within first month of life Recurrent bacterial infections by 3 months Splenomegaly is not uncommon. Majority of WAS children develop at least 1 autoimmune disorder and cancer (lymphoma and leukemia) Thrombocytopenia Bleeding = major cause of death **Triad: Thrombocytopenia, eczema, recurrent infections (defective humoral and cellular immunity) "WASP sting = reaction on skin = eczema" "WAITER" = Wiskott-Aldrich Immunodeficiency, Thrombocytopenia, Eczema, Recurrent pyogenic infections Epidemiology: MALES only (Children) (since X-linked recessive) Lab: Normal levels of T and B cells but poor Ab response. Low platelet count. IgM and IgG decreased, IgA and IgE elevated. (If you drink Wisk-ey, your Ethyl Alcohol goes up and your Mental function and Gait goes down) Tx: HSC

MHC II def/ Bare Lymphocyte syndrome II

Defective HLA II expression, failure of CD4+ cells development "Syndrome II = MHC/HLA II effected" Defective HLA II expression results in defects in transcriptional regulators essential for expression of genes in the HLA II locus (ex: Class II transactivator (CIITA)) MHC class II is necessary for CD4+ helper T cell activation and cytokine production. No CD4+, no helping B-cells and CD8 T-cells.

MPO deficiency

Defective MPO results in defective production of HOCl or HClO (hypochlorous acid = bleach) from H2O2. Without MPO, we can't make HOCl or HClO which means we can't kill the organism. Immune deficiency, esp. Candida albicans infection Most common primary disorder of phagocytes, but majority are asymptomatic Labs: NBT test is normal because NADPH oxidase is intact. Respiratory burst (O2 to H2O2) is intact.

Chronic Granulomatous Disease (CGD) immunological problem

Defective NADPH oxidase

Hyper IgE (Job) Syndrome

Defective STAT3 signaling (one DIRECT; one INDIRECT) → impaired IL-6, IL-10, IL-21 signaling so Th17 differentiation is reduced (less neutrophil/macrophage chemotaxis) *T-cell affected "Reverse the 3 in Stat3 and you get IgE" Skewing of Th response away from Th17/toward Th2 results in high IgE levels - Other Ab levels normal -T cell, B cell counts normal -eosinophilia Lack of IL-10 = inappropriate inflammation Defective STAT3 in keratinocytes → reduced defensin production on skin Paradox: patients with type I form have decreased allergies (likely due to impaired mast cell/basophil degranulation) Impaired recruitment of neutrophils to site of infection ABCDEF acronym: •Cold, non-inflamed staphylococcal Abscess •Retained by Baby teeth •Coarse facies •Dermatologic problems - eczema •Increased IgE •Fractures from minor trauma Complication: pneumonia, blisters, abscesses Recurrent candida infections, pneumonia, eczema. Facial, dental, and skeletal problems. "FATED" = Facies/fractures, abscesses, baby Teeth, hyper IgE/Eosinophilia, dermatologic (severe eczema) Treatment: long term antibiotic therapy and immunoglobulins

SCID (severe combined immune deficiency)

Defective cell-mediated and humoral immunity No cytokine signaling⇒ Ø maturation of B and T cells ⇒ can't fight infections "Combined = BOTH B and T effected" Opportunistic: fungal, viral, bacterial, protozoal s/sx: presented as infants Protracted diarrhea Candidiasis, pneumocystis, pseudomonas, CMV, varicella, et Failure to thrive No T Cells ⇒ GVHD like symptoms: thrush, severe diaper rash, and failure to thrive. Also, diarrhea, cytopenia, elevation of liver Classic symptoms who are not dx in the neonatal period: recurrent severe infections, chronic diarrhea, and failure to thrive. Labs: low lymphocyte absolute count XRAY: absent thymic shadow Quantitative PCR: Decreased T-cell receptor excision circles (TRECs) (detection of TRECs in newborn screening for SCID) No live vaccines Fatal within 1 yr if not treated, appears normal at birth b/c of mom's Igs Treatment: Sterile isolation "bubble baby" and stem cell transplantation Strict hygiene measures, gene therapy, and prevention by isolation from potential sick contacts

Selective IgA deficiency

Defective isotype switching from IgM to IgA Ex: Celiac disease - IgA deficiency "Selective IgA deficiency = therefore only IgA is abnormal (decreased)" "6 A's of IgA deficiency = Asymptomatic, Airway infections, Anaphylaxis to IgA containing products, Autoimmune diseases, Atopy" *B-cell is affected. •Lack of secretory IgA largely compensated for by pentameric IgM on mucosal surfaces •Other antibody isotypes also made more abundant •Mucosal immunity not severely affected •Decreased serum and mucosal IgA with normal IgG and IgM. Increased risk for mucosal infection, especially viral (IgA is normally on the mucosal surface of the GI tract). However, majority are asymptomatic. Symptomatic patients have •Airway and mucosal infections (recurrent sinopulmonary infections) •Autoimmune disease •Atopy •Anaphylaxis to IgA-containing products - transfuse blood with IgA •Increased risk for Giardia •Food allergy, diarrhea, GI infections •Atopic diseases, anaphylaxis to blood transfusion; fat malabsorption. **Most common immunoglobulin deficiency

Chediak-Higashi syndrome immunological problem

Defective lysosomal trafficking regulator (LYST defect) Protein trafficking defect characterized by impaired phagolysosome formation Defect in neutrophil chemotaxis and microtubule polymerization dysfunction → defective phagosome-lysosome fusion Autosomal recessive "Che che - like a train has a LYST 'list' of dysfunctions on the railroad on the ALPINe slope" "ALPINe = Albinism, Lymphohistiocytosis, Peripheral Neuropathy, Infections, Neurodegeneration/neutropenia"

Leukocyte adhesion Deficiency Immunology problem

Defective migration of PMN, monocytes from blood to infection sites "No rolling or adhesion" Autosomal recessive defect of integrins (CD18 subunit) 3 types: Type I Defective CD18: subunit of LFA-1, CR3, CR4 - Defective binding to ICAM-1 (no tight binding) leads to defective uptake of opsonized pathogens Type II Defective sialyl-Lewis X carbohydrates - Defective binding of E-selectin (no rolling adhesion) Type III Defective intracellular proteins - Defective activation of surface adhesion molecules in response to ligand binding (ex. LFA-1 binding of ICAM-1) so tight binding cannot occur.

Post-transfusion purpura (PTP)

Delayed adverse reaction to a blood transfusion or platelet transfusion that occurs when the body has produced alloantibodies to the allogeneic transfused platelet's antigens. *Presents 5-12 days AFTER transfusion = potentially fatal

Vitamin K deficiency

Disrupts factors II, VII, IX, X, proteins C and S (2, 7, 9, 10, C, S) *factor II = prothrombin "CS states 2 + 7 = 9 'not' 10!" SNTT - 7,9,10,2 (read as 'snot') "No K-leenex to Clean Some SNTT" Epidemiology: 1. Newborns - lack of GI colonization by bacteria that normally stabilize vitamin K. 2. Long-term antibiotic therapy - disrupts vitamin K producing bacteria in the GI tract 3. Malabsorption - leads to deficiency of fat-soluble vitamins, including vitamin K 4. Obstruction of bile ducts or liver disease *Note that most blood-clotting factors are made in the liver so diseases of the liver can also lead to a tendency to bleed. Pathogenesis: 1. Vitamin K is a fat soluble vitamin that is activated by epoxide reductase in the liver. 2. Activated Vit K gamma carboxylates factors 2, 7, 9, 10, C, and S. *gamma carboxylation is necessary for factor function (adds a carboxyl group to glutamic acid residues) Prothrombin is a plasma protein that is formed by the liver oCoagulation becomes deficient within a day if liver production of prothrombin stops. oLiver needs Vitamin K for normal prothrombin levels. o↓ Vitamin K = ↓ prothrombin = ↓ coagulation. ↓ Vitamin K = ↓ prothrombin Tx/prevention: Vitamin K injection given prophylactically to all newborns at birth to prevent hemorrhagic disease of the newborn. Vitamin K injections also given preoperatively to surgical patients with liver disease or obstructed bile ducts.

Immune Deficiencies in Hereditary and Metabolic Disease:

Down syndrome Increased susceptibility to respiratory infection Increased incidence of leukemia Increased incidence of autoimmune disease Sickle cell disease Decreased spleen function; autosplenectomy Defective opsonization Alternate complement pathway dysfunction Turner syndrome Frequent respiratory infections; bronchiectasis Decreased T lymphocyte numbers; low Ig levels Cystic fibrosis Pneumonia; lungs colonized with Pseudomonas aeruginosa Adaptive immunity normal; innate immunity impaired Diabetes Increased susceptibility to infections Lymphopenia; impaired proliferation; anergy Normal antibody responses Decreased phagocytic adherence, chemotaxis, phagocytosis and bactericidal activity Uremia Decreased serum IgG and response to vaccines Increased T cell apoptosis; decreased proliferation; decreased chemotaxis and phagocytosis.

IFN-γ receptor (IFN-γR) and IL-12 receptor deficiency

Either deficiency impairs the ability of macrophages to kill intracellular pathogens. IFN-yR deficiency causes the same effects as listed below: Innate: Defective IL-12R on NK cells prevents mutual activation between macrophages and NK cells Adaptive: Defective IL-12R on CD4 T cells prevents differentiation into TH1 cells. As a result, IFN-y is not secreted, preventing CTLs from reinforcing TH1 cell and macrophage response Pathogenesis: Receptors for IFN-y are composed of a dimer of IFN-yR1 and IFN-yR2, crosslinked by the ligand IFN-y, which must bind to the R1 chain for signaling to be triggered. IFN-y normally activates macrophage, promotes B-cell class switching from IgM to IgG, promotes Th1 phenotype and inhibits Th2 phenotype. Clinical: Recurrent **Mycobacteria and **Salmonella infections. Skin infections, swollen lymph nodes, bloodstream infections Many become ill after receiving live BCG TB vaccination that is given routinely at birth in many countries (not US) (Th1 - intracellular pathogens - key cytokine for Th1 = IFN-gamma and IL-12. Activates Macrophages and NK cells.) (TB injection = u get a bump on the skin and if it stays = granuloma = related to macrophages) *T-cell affected. Genetics: Recessive and dominant mutations in the IFN-y receptor causes diseases of differing severity. -Recessive: Mutant alleles of IFN-yR1 produces a mutant chain that cannot reach the cell surface. Homozygous recessive patients only have IFN-yR2 on the surface and cannot react to the IFN-y ligand. Heterozygotes can produce enough wildtype IFN-yR1 chains to produce enough functional receptor dimers. -Dominant: The mutation lies in a lack of signaling domain. Therefore, the receptor is nonfunctional even with sufficient receptor dimerization. Dominant Negative mutation.

HIV/AIDS Labs

Enzyme-Linked Immunosorbent Assay (ELISA): •Presumptive test for the presence of antibodies to HIV. (the antigen) •Uses the patient's serum added to a known antigen. If IgG antibodies are present in the patient's serum, they will bind to the antigen. •Another antibody to human IgG is added which attaches to the patients IgG antibodies. (enzyme- linked). A substrate for the second antibody is added which will change color if antibodies are present. Western Blot Test: •Confirmatory test for the presence of antibodies to HIV. •Viral proteins from HIV are separated by Acrylamide gel electrophoresis and are transferred (blotted) from the gel onto paper. •The patient's serum is added, and HIV antibodies bind to the viral proteins. Enzyme-labeled antibodies to human IgG are added. An enzyme substrate is then added, and color bands appear at the location of viral proteins. Lab results: •Lymphocyte count = determine the rate of immunosuppression •As the erosion of lymphocytes continues to decline, opportunistic infections ensue, responsible for approx. 70% of deaths. •During the early phases of the disease and during the chronic phase, the CD4+ T-Cell counts exceed 500/mm3. As the disease progresses, helper T-cell counts decrease. •Once the number of CD4+ T-cells falls below 200/mm3, the crisis phase ensues. In the last stages of the disease, almost no CD4+ cells are present in the circulation

Factor D or Factor P (properdin) deficiency

Factor D or Factor P defect → impaired formation of C3b → impaired opsonization and MAC complex Factor D and Factor P are seen in the alternative pathway. Factor D is used to cleave C3bFactorB to make C3bBb (alternative C3b convertase). Factor P is used to stabilize this alternative C3b convertase (C3 → C3a and C3b). If there is a problem with Factor D or Factor P, there will be an impaired formation of C3b, which will impair formation of C5 convertase, which can impair formation of the MAC complex. C3b impairment can also impair opsonization. Susceptibility to pyogenic infections.

Factor I defect

Factor I defect → depleted C3 supplies (C3 deficiency) → impaired opsonization Normally, Factor H is a regulator of complement activation that blocks the formation of C3 convertase and is a cofactor for cleavage of C3b by factor I. If there is a defect in factor I, C3b can't be cleaved to become inactivated C3b (iC3b). This will lead to the conversion of C3 to C3b to proceed unchecked. Eventually, the C3 supplies will be depleted (C3 deficiency). When this happens, we can't get anymore C3b and can't opsonize. (we don't want to make so much convertases and run out of the C3 in the blood) ("tag 10% on bacteria but waste 90%") Note that Factor I also cleaves C4b to iC4b. Susceptibility to pyogenic infections.

Thrombotic thrombocytopenia purpura (TTP)

Functional loss of a degrading enzyme (ADAMTS13) of ultra-large multimers of von Willebrand factor (ULvWF) Loss can be due to inherited mutation of the ADAMTS13 gene or acquired antibody inhibition. Acquired antibody cause is through immune microangiopathic malaria Decreased ADAMTS13 is usually due to an acquired autoantibody; most commonly seen in adult females. Functional loss of ADAMTS13 to break down ULvWF multimers (not typical size of vWF) → abnormal platelet adhesion → platelet thrombosis (clot) on vessel wall (microthrombi) → consumption of platelets to make microthrombi leads to low platelets blood stream and the clot will shear the RBC → MAHA Characterized by purpura (thrombocytopenia); microangiopathic hemolytic anemia; and **CNS organ involvement (CNS is specific for TTP) *Petechiae, ecchymoses MAHA and thrombocytopenia without another apparent cause. Thrombocytopenia with increase bleeding time Normal PT/PTT (coagulation cascade not activated) Anemia with schistocytes ↑ Megakaryocytes in bone marrow biopsy Tx: Plasmapheresis with plasma replacement (plasma exchange) = definitive therapy. -Avoid platelet transfusions

Prothrombin gene mutation (prothrombin G20210A)

G20210A mutation in 3' untranslated region (3' UTR) of the prothrombin gene ⇒ mRNA accumulation → increased prothrombin levels Autosomal dominant "Go Away 2021" Increased prothrombin ⇒ thrombus (increased risk of venous thrombosis)

Glanzmann thrombasthenia

Genetic GPIIb/IIIa deficiency Autosomal Recessive or acquired as an autoimmune disorder "There are 2a's and 3n's in Glanzmann = GP2b/3a" Pathogenesis: GPIIb/IIIa is needed for fibrinogen linking between 2 platelets → without it, platelet aggregation is impaired. •GpIIb-IIIa integrin receptor is activated when the platelet is stimulated by ADP, epinephrine, collagen, or thrombin. GpIIb/IIIa is essential to blood coagulation since the activated receptor has the ability to bind fibrinogen (as well as von Willebrand factor, fibronectin, and vitronectin), which is required for fibrinogen-dependent platelet-platelet interaction (aggregation). As a result, no fibrinogen bridging of platelets to other platelets can occur, and the bleeding time is significantly prolonged. •In contrast, GPIb receptors are normal with Glanzmann's thrombasthenia, unlike in Bernard-Soulier syndrome. Clinical: •Patients present from birth with easy bruising, excessive bleeding, petechiae, hematomas, epistaxis, and heavy menstrual flow. Older - GI bleed. No platelet aggregation with normal platelet count. Labs: Light transmission aggregometry (LTA) is widely accepted as the gold standard diagnostic tool for assessing platelet function. Centrifuged platelet-rich plasma samples are monitored before and after the addition of an agonist (ADP, collagen, epinephrine, arachidonic acid, ristocetin, thrombin receptor activating peptide, and thromboxane A2 mimetic), assessing shape change, lag phase, percent of aggregation, slope of aggregation, and deaggregation. This test is highly specific for GT, as platelet aggregation fails to occur with any agonist, except ristocetin, where the reaction is preserved. •Normal results from ristocetin assay**** •Essentially, this platelet disorder fails platelet aggregation tests (or have an abnormal ristocetin assay) as long as there is an addition of ADP, collagen, epinephrine, or arachidonic acid.

Bernard-Soulier syndrome

Genetic GPIb deficiency Autosomal Recessive "There is only 1b in Bernard Soulier (Gp1b)" Platelets use GPIb (receptor for vWF) to adhease to vWF. If they can't, they would die, resulting in thrombocytopenia. •Patients present from birth with easy bruising, excessive bleeding, petechiae, epistaxis, and heavy menstrual flow Labs: Blood smear = mild thrombocytopenia with enlarged platelets (getting more immature) "Big Suckers" = enlarged platelets •Gp1b ↓ PT & PTT usually normal •Platelets cannot adhere to site of injury. No platelet aggregation in ristocetin assay

Hemophilia B

Genetic factor IX (9) deficiency - X-linked recessive - ~10% of women who are carriers manifest clinical symptoms of bleeding due to X-inactivation (lyonization). •"The Royal Disease" •75% of patients have a missense substitution "B9" = "benign" Predominantly MALES •Incidence: 1 in 20,000 males Coag deficiency in intrinsic pathway Labs: ↑ PTT and normal PT ↓ factor IX Normal platelet count and bleeding time Tx: Recombinant factor 9 Recombinant proteins now available but expensive

Hemophilia A

Genetic factor VIII (8) deficiency - X-linked recessive - ~10% of women who are carriers manifest clinical symptoms of bleeding due to X-inactivation (lyonization). - Can arise from new mutation without any family history -Carriers have 50% plasma FVIII levels, if this drops below 40% due to skewed X-inactivation, they may have clinical features of mild hemophilia. -Of those who have severe deficiency (defined as <1% activity of factor VIII), 45-50% have the same mutation, an inversion within the factor VIII gene that results in total elimination of protein production. (Exchange between F8A in intron 22 and extragenic F8A.) *There are 2 components to factor VIII and the smaller component is seen here. "Aight = Eight" Predominantly MALES •Incidence: 1 in 5,000 males •Most common inherited coagulation disorder Coag deficiency in intrinsic pathway Deficiency in factor VIII due to mutations in the F8 gene on the X chromosome Labs: ↑ PTT and normal PT ↓ factor VIII ***Normal platelet count and bleeding time Tx: Recombinant factor VIII (8) Recombinant proteins now available but expensive Desmopressin (DDAVP) *Hemophilia A vs Von Willebrand: Bleeding time in hemophilia A is NORMAL b/c platelets aren't affected. Bleeding time in von Willebrand is INCREASED b/c platelets are affected.

Hemophilia C

Genetic factor XI (11) deficiency Autosomal Recessive •Two-point mutations account for 90% of disease in the Ashkenazi Jewish population; carrier rate of ~5% -Nonsense mutation Glu117X; homozygotes lack factor XI protein. -Missense mutation Phe283Leu causes a defect in dimer formation, resulting in poor secretion; homozygotes have ~10% of normal plasma factor XI activity •Compound heterozygotes for Glu117X and Phe283Leu have activity of ~3%, whereas heterozygotes for either mutation have activities of 50% to 60%. Founder Effect: Ash. Jews Founder effect: loss of genetic variation that occurs when a new population is established by a very small number of individuals from a larger population (tend to not recruit newcomers and tend to marry within community) - If not from this population, it occurs in 1:100,000 Coag deficiency in intrinsic pathway Deficiency in factor XI due to mutations in the F11 gene on chromosome 4 •Mutations in the F11 gene result in a shortage (deficiency) of functional factor XI. This deficiency impairs the coagulation cascade, slowing the process of blood clotting and leading to the bleeding problems associated with this disorder. The amount of functional factor XI remaining varies depending on the particular mutation and whether one or both copies of the F11 gene in each cell have mutations. Clinical: Oral cavity, tonsils, and Urinary tract after injury No spontaneous bleeding •Bleeding from oral cavity, tonsils, urinary tract after injury •Spontaneous bleeding uncommon •The most mild and most rare of the hemophilias Tx: Recombinant factor 11

Von Willebrand disease

Genetic vWF deficiency (most common inherited coagulation disorder) -Multiple subtypes, causing quantitative and qualitative defects; most common type is autosomal dominant with decreased vWF levels. Platelet defect: low vWF cannot adhere platelets to the site of endothelial injury. Coagulation defect: low vWF cannot protect factor VIII Most common among Caucasian Pathogenesis: vWF is large multimeric plasma glycoprotein released by endothelial cells to mediate platelet adhesion and stabilize factor VIII. Weibel-Palade bodies store vWF and P-selectin. Reduction in vWF slows formation of blood clots → prolonged bleeding episodes. Clinical: Mild mucosal and skin bleeding; low vWF impairs platelet adhesion •Mucous membrane bleeding (nose, GI, heavy menstrual bleeding), excess blood loss following trauma or surgery. Muscle bleeding rare *Can be seen in secondary hemostasis problem b/c we need vWF to stabilize factor VIII (extend half life from 1-2 hours to 8-12 hours) *There are 2 components to factor VIII and the larger component is seen in von Willebrand disease. Labs: ↑ bleeding time (no platelet adhesion) ↑ PTT and normal PT (decreased factor VIII half life as vWF normally stabilizes it) Abnormal ristocetin test: - Ristocetin test induces platelet agglutination by causing vWF to bind platelet GPIb. The lack of vWF impairs agglutination → abnormal test VIII↓ vWF↓ BT↑ Tx: Desmopressin (ADH analog) - increases vWF release from Weibel-Palade bodies of endothelial cells.

Refeeding syndrome

If a child has been malnourished and is suddenly given a large meal (rapidly reintroducing to a starving child) = DEADLY First week of refeeding is most dangerous Sudden increase in carbohydrates can cause death Sudden increase in proteins can cause damage to the liver (Kwashiorkor)

Chronic Mucocutaneous Candidiasis (CMC)

Immune deficiency in Th17 cells Multiple etiologies but most common: overactive transcription factor (STAT1) in >50% of cases. CMC characterized by recurrent or persistent symptomatic mucocutaneous infections caused by FUNGI (Candida) "Order a CMC STAT3 → (Th)1" STAT3 activity overridden by STAT1 activity → skews Th cell differentiation from Th17 to Th1 → Leads to diminished antifungal response Th17 normally fights fungals •Nails, skin, oral, and genital mucosa affected •Mild staphylococcal skin infections •Recurrent mucocutaneous herpes virus disease •Milder autoimmune disease (thyroid autoimmunity) Epidemiology: CMC seen in several conditions, including newborns, those with T-cell deficiencies (e.g., AIDS, several primary immunodeficiencies, immunosuppressive drugs, others) and those on broad spectrum abx. •Rare condition

Types of containers (prevent clotting outside body)

In glass containers, blood clots in about 6 minutes. Siliconized containers take 1 hour or more. The silicone prevents activation of platelets and factor XII

Drug-induced thrombocytopenia (DITP)

Induced and/or perpetuated by presence of a drug or other ingested substance (e.g. QUININE; walnuts) Clinically indistinguishable from ITP b/c has thrombocytopenia and bleeding symptoms. LOOK AT DRUG USE.

HIV/AIDS morphology

Initial: •The morphologic changes induced by HIV are relatively non-specific, vary with time and with the extent of the viremia, and the degree of immunosuppression. •The lymph nodes initially enlarge and show hyperplasia of the follicles, reflecting the B-cell response to viral antigens that leads to the appearance of antiviral antibodies. Later: •After some time, the lymph nodes involute and become depleted of lymphocytes, especially in the T-cell dependent parafollicular zones. •In the last stages of AIDS, the lymph nodes may be infected with Fungi or Mycobacteria, which usually do not provoke an inflammatory response, and almost never contain granulomas due to a lack of immune cells.

Chediak-Higashi syndrome labs and treatment

Labs: Neutropenia - due to intramedullary death of neutrophils (can't divide properly) -Due to microtubule defect, it can't divide and just dies before being able to leave to the blood. Giant granules in kidneys - Granules normally get distributed by the "railway" system, but without it, the granules pile up next to the Golgi (defective degranulation as well) -delayed microbial killing (affected leukocytes and platelets contain giant granules) -See giant cytoplasmic granules in all granule containing cells → worthless platelets and useless granulocytes Tx: Early bone marrow transplant

Chronic Granulomatous Disease (CGD) labs and tx

Labs: Nitroblue tetrazolium test = screen for CGD. Leukocytes are incubated with NBT dye, which turns BLUE if NADPH oxidase can convert O2 to O2-. It remains COLORLESS if NADPH oxidase is defective. Tx: Life-long prophylactic antibiotics IFN-gamma Bone marrow transplant Gene therapy

Wells criteria for DVT: (each item below gets 1 point)

Leg symptoms and findings 1. calf swelling > 3cm (compared to other leg) 2. Swollen unilateral superficial veins 3. Unilateral pitting edema 4. Swelling of the entire leg 5. Localized tenderness along the DVT History 1. Previous documented DVT 2. Active cancer or treatment in previous 6 months 3. Paralysis, paresis, recent cast immobilization of legs 4. Recently bedridden for > 3 days or major surgery 5. Alternative explanation for leg symptoms at least as likely (-2) 0-1 points = DVT unlikely, check D-dimer >1 point = DVT LIKELY, check Doppler US

Common variable immune deficiency (CVID)

Low immunoglobulin/ Hypogammaglobulinemia (↓ IgM, IgA - usually all classes but sometimes only IgG) due to B-cell (make Ig) or helper T-cell (make IL-4/IL-5) defects Most common type of primary immunodeficiency DC, NK cells, macrophages may be affected. Unknown cause - some genetic. *Unique is that EVERYTHING (all Ig) is LOW. *B-cell is affected Epidemiology: later than other B-cell defects (20-40 y/o) B cells are phenotypically normal but unable to differentiate into Ig-producing cells (LOW PLASMA CELLS), resulting in low Ig of all classes. Recurrent sinopulmonary bacterial infections •Enterovirus causing meningoencephalitis •Giardia lamblia - persistent diarrhea •High incidence autoimmune disease •Increased risk for lymphoma

Bare Lymphocyte syndrome I

MHC I deficiency = defective TAP protein in MHC I processing/presentation pathway Peptides produced by proteasomes unable to enter ER and be loaded onto MHC I molecules MHC I expression on cell surfaces <1% of normal Patient mounts feeble CD8 T cell responses "Syndrome I = MHC I" (later you see syndrome II = MHC II" Normally, proteasomes cleave protein into peptide fragments in the cytoplasm which are taken up by TAP (surface molecule on ER) → A peptide delivered by TAP binds to the class I heavy chain, forming mature MHC class I molecule. → MHC I dissociates from peptide loading complex and exported from the ER → Gets transported to Golgi → Gets into secretory vesicle → MHC I with the peptide is finally displaced on cell surface → CD8 T cell response. •Recurrent bacterial infections in lungs and airways → can lead to bronchiectasis (which damages the passages leading from the windpipe to the lungs (bronchi) and cause breathing problems) •Open sores (ulcers) on the skin (face, arms, legs) •Some people are asymptomatic.

Overnutrition

More fat cells = more leptin Increased adipose → increase leptin → increase activity and less hunger (body is telling you to lose weight). More leptin signals to decrease glucocorticoid levels Decreased glucocorticoids → decreased thymocyte apoptosis → hyper-inflammatory immune response. Obesity is disease of chronic inflammation since increased adipose tissue increases release of proinflammatory adipokines (IL-6 stimulates release of C-reactive protein and TNF-alpha) and decrease anti-inflammatory adipokines (adiponectin and IL-10)

Chronic Granulomatous Disease (CGD) pathogenesis

NADPH oxidase normally converts O2 to O2-. Lack of O2- production prevents the ability to lower pH in phagosomes so antimicrobial compounds can't function. Decreased reactive oxygen and decreased respiratory burst in neutrophils → increased susceptibility to catalase (+) organisms (Staph, pseudomonas, Serratia)

Why COVID-19 patients develop blood clots:

Neutrophils release NETS (neutrophil extracellular traps), which are webs of chromatin, microbicidal proteins, and oxidant enzymes. Normally, they contain infections but when they are unregulated, they can promote inflammation and clotting. COVID-19 infection also correlated with higher levels of von-Willebrand Factor and lower levels of ADAMTS13 (which is involved in vWF regulation)

X-linked SCID (common gamma chain)

No Jak3⇒ defective IL-2R gamma- Gamma globulin coding gene mutations Common gamma chain deficiency ⇒ no receptors for IL 2/4/7/9/15/21 Prevents cytokine receptors from interacting with Jak3 signaling protein X-linked Recessive- boyzz MOST COMMON SCID

Leukocyte adhesion Deficiency Pathogenesis

Normal immunology to recruit neutrophils: 1. There is rolling adhesion of the neutrophils 2. To recruit the neutrophils into the infection sites, there are factors to allow tight binding. 3. Neutrophils have LFA-1 (subunit of CD18) which binds to ICAM-1 of endothelial cells. There is also E-selectin on the endothelial surface which binds to sialyl-Lewis X to further help with the rolling adhesion. ^problems with any of these components = no recruitment of neutrophils.

Chediak-Higashi syndrome pathogenesis

Normally, bacterium is phagocytosed by neutrophil → phagosome fuses with azurophilic and specific granules → pH of phagosome rises which leads to activated antimicrobial response by recruiting lysosomes → bacterium is killed. ^problem is can't phagocytose and can't recruit lysosomes ^ Defective LYST protein prevents fusion of lysosomes with endosomes. There is a problem with the "railroad" system made of microtubules. The phagosome can't merge with lysosomes to make the phagolysosome.

Disseminated intravascular coagulation (DIC) pathogenesis

Pathologic activation of the coagulation cascade •Sources of tissue factor include sepsis, obstetrical complications, acute progranulocytic leukemia, severe burns, severe trauma, transfusion reactions, snake bites, transplant rejection → inappropriate introduction of tissue factor (like endotoxin) generates a hyperthrombinemic state → activates factor VII and complexes with it → activates factor X → activates prothrombin → becomes thrombin → wide spread activation of coagulation → fibrin clots thrombotic disorders like DVT and PE •Fibrin clots also consume platelets and clotting factors which leads to thrombocytopenia and CF deficiency → eventual bleeding •So, we see thrombotic disorders first, then bleeding later.

Disorder of fibrinolysis

Plasmin overactivity → want to cleave the clot but instead result in excessive cleavage of serum fibrinogen. 1. Radical prostatectomy - release of urokinase activates plasmin 2. Cirrhosis of liver - reduced production of α2-antiplasmin Labs: Increased bleeding (similar to DIC) ↑ bleeding time ↑ PTT/PT Increased fibrinogen split products WITHOUT D-dimers. (serum fibrinogen is lysed rather than cross-linked fibrin from fibrin thrombi) Tx: Aminocaproic acid (blocks activation of plasminogen)

Heparin Induced Thrombocytopenia (HIT)

Platelet destruction that arises secondary to heparin therapy (occurs 5-14 days after beginning) Heparin is a very NEGATIVELY-CHARGED conjugated polysaccharide that catalyzes effect of antithrombin III by 100x or 1000x (prevents clots/promotes bleeding) •Antibodies (IgG) bind to Heparin, which binds platelet factor PF4. This complex binds to platelets → additional platelet activation, release, and aggregation → thrombosis Also, the complex + platelet combo is recognized as foreign so it is removed by splenic macrophages → thrombocytopenia. *Note there is endogenous heparin that is found at low levels. It is produced by basophilic mast cells particularly in the lungs and to a lesser extent in the liver. Both venous and arterial thromboses occur, even in setting of marked thrombocytopenia. - May cause severe morbidity (e.g., loss of limbs) and death. Labs: Low platelet count AND Thrombosis. (>50% reduction in platelet count for HIT-2 = more serious and switch to argatroban) (if minor reduction in platelet count = HIT-1 = less risk for thrombosis) Treatment: Stop Heparin therapy and Do not use Heparin or LMWH if there is a history of HIT. If HIT occurs or has occurred previously in a patient, IV direct thrombin inhibitor such as argatroban is indicated.

Fetal and/or neonatal alloimmune thrombocytopenia (NATP)

Pregnant woman produces an alloantibody that reacts with paternal platelet-specific antigen carried on fetal platelets. -Mother sensitized following blood transfusion or during pregnancy. -Maternal IgG antibodies cross placenta and react with corresponding antigens on fetal platelets → neonatal thrombocytopenia

Chediak-Higashi syndrome clinical

Progressive neurodegeneration, peripheral neuropathy (seizures, weakness, gait disturbances): need the railroad system to transmit nerve signals from the spine to the periphery. (partial) Albinism - the pigmentation is by melanocytes but can't be passed on to keratinocytes which results in albinism Recurrent pyogenic infections - Since the phagosome can't merge with lysosome and even there is a decrease in phagocytosis, the bacteria can't be destroyed. Bleeding disorders (defective primary hemostasis) - due to abnormal dense granules in platelets Accelerated phase → lymphoma.

Undernutrition

Prolonged undernutrition = increased glucocorticoids Increased glucocorticoids suppress the immune system. Less fat cells = less leptin In severe malnutrition, you want to stop the immune system from working and focus on the brain. Low leptin levels act as a hormone to signal the thymus to ATROPHY. Thymus atrophy = failure of new T cells to mature = less cell-mediated immunity = less antibody response. Spleen, bone marrow, and lymph nodes adversely affected

Omenn (RAG/ Artemis)

RAG1 or 2 mutation → prevent VDJ recombination, which interferes with proper T and B cell maturation "RAG(s) are OMEN(s) as it causes you to scream "EEE" - eosinophilia and high IgE and effect EEEverything" (remember this is different from hyper IgE b/c only T-cells affected there and in this one, both B and T cells affected) No VDJ recombination for Ig/TCR⇒ decrease or faulty production of B and T cells Y'ALL: no recomb means no antibodies.. Got it? Okay! Move on Recombination-activating genes (RAG) bind to flanking V,D,J regions, introducing dsDNA breaks which are then repaired to non-homologous end-joining pathways. Eosinophilia, high IgE, low TCR diversity Labs: low B/T cells The expanded T cell clones in this disease consistently exhibit a Th2 phenotype with secretion of IL-4 and IL-13 = IgE isotype switching. s/sx: tumors, radiation sensitivity, neuro problems Autosomal recessive

G6PD deficiency

Related to the neutralization of H2O2 if we are not trying to generate HOCl from MPO. Defective G6PD → can't generate NADPH African Variant = mildly reduced half life of G6PD → mild intravascular hemolysis with oxidative stress. Mediterranean variant = markedly reduced half life of G6PD → marked intravascular hemolysis with oxidative stress. Heterozygote carrier = protective against falciparum malaria. H2O2 + GSH → GS-SG GS-SG recycled back to GSH to continue neutralizing H2O2 by NADPH, which is produced by G6PD. *GSH = glutathione (antioxidant) X-linked recessive disorder = Reduced half-life of G6PD = less NADPH = no ability to regenerate GSH = increased oxidative damage. Increased risk for Oxidative stress: - Infection, drugs (primaquine, sulfa drugs, dapsone), fava beans (Med. diet) Hemoglobinemia, Hemoglobinuria and back pain hours after exposure to oxidative stress *Self-limited → Hemolysis stops when only young red cells are left. 1. Intravascular hemolysis - Heinz bodies; precipitate damage membrane 2. Extravascular hemolysis - Heinz bodies attach to cell membranes to decrease erythrocyte deformability. Bite cells created. Loss of membrane → spherocytes. Cells become trapped → erythrophagocytosis. Oxidative stress precipitates Hb as Heinz bodies, which are removed from RBCs by splenic macrophages → bite cells on blood smears. (RBC with a "bite mark") Heinz preparation = screen for disease Enzyme studies = confirm deficiency (performed weeks after hemolytic episode resolves b/c if perform during, those lacking enzyme are dead and remaining RBCs have the enzyme)

Hemolytic uremic syndrome (HUS)

STEC are common intestinal bacteria in cattle and outbreak results from contaminated water, beef products, vegetables, and other food groups. "STEC = STEAK" This is a primary cause of TMA syndrome and most important secondary cause of HUS is Shiga-toxin producing E. coli (STEC) Seen in children <5 y/o (2-5 especially) o Children < 5 y/o → E. coli (O157:H7) (Shiga-like toxin) → Shiga toxin: bloody diarrhea, enters circulation and binds to the glomerular capillary, endothelial cells, mesangial cells, glomerular tubular epithelial cells, and tubular epithelial cells (so can potentially affect the renal system). The binding to the cells can lead to cell apoptosis. o The toxin is also pro-inflammatory and pro-thrombic → encourage endothelial secretion of von Willebrand factor → platelet aggregation in blood vessel. Characterized by thrombocytopenia, MAHA, and acute kidney injury Diarrhea → abdominal pain, fever, vomiting → BLOODY DIARRHEA Black urine then oliguria and then anuria. CNS alterations if severe. *be careful because in questions, there might be petechiae noted. However, the key parts that help distinguish is the fever, and renal dysfunction (hematuria, proteinuria, increased BUN and increased creatinine) Leukocytosis Renal failure** Thrombocytopenia with increase bleeding time Normal PT/PTT (coagulation cascade not activated) Hemolytic Anemia with schistocytes ↑ Megakaryocytes in bone marrow biopsy Supportive, dialysis (50%), electrolyte correction, HTN management; hemodialysis

Protein S deficiency

Same thing- protein S is a cofactor for activated Protein C •Can either be hereditary (autosomal dominant) or acquired due to vitamin K deficiency, pregnancy, liver disease, or even treatment with coumadin. •Protein S is a vitamin K dependent anticoagulant which acts as a cofactor to activated protein C (aPC) in the proteolytic degradation of factor V. •Either decreased levels or impaired function leads to decreased breakdown of factor V promoting venous thrombosis and P.E., with a clinical presentation similar to protein C deficiency. Protein S is a cofactor for the anticoagulant activity of APC. Only the 40% of protein S that is the free fraction is functionally active as a cofactor for APC. Clinical presentation similar to protein C deficiency 50% reduction in PS → clotting cascade can't be turned off because APC cannot function. Dx via protein measurement. 40% is free in plasma and available as a cofactor DO NOT GIVE WARFARIN

D-Dimer assays

Sensitive but not specific for intravascular thrombosis Negative assay = rule out DVT Positive assay = will NOT help you rule in a blood clot D-dimer is created from the splitting of CROSS-LINKED FIBRIN of blood clots. A normal D-dimer is considered less than 0.50 or <500 ng/mL. A positive D-dimer is 0.50 or greater. Since this is a screening test, a positive D-Dimer is a positive screen.

Chronic Granulomatous Disease (CGD) clinical

Since we can't convert O2 to superoxide (O2-), we get recurrent infection with catalase-positive organisms (Staph. Aureus, E. coli, Pseudomonas cepacia, Serratia marcescens, Nocardia, and Aspergillus) Pts with CGD don't have problems with some bacteria because some makes H2O2 which compensates in the pathway. HOWEVER, some bacteria make catalase (hence catalase positive bacteria), which destroys the natural H2O2 → makes pts with CGD susceptible to infection. Macrophage rich chronic inflammation reaction at the site of infection since neutrophil defense is inadequate → granuloma formation. *Children with recurrent resp infection, LAD, inflammatory and PUSTULAR LESION (not eczema = not WAS)

Leukocyte adhesion Deficiency Clinical and treatment

Skin and mucosal bacterial infections persistent and recurrent despite use of antibiotics and generation of B and T-cell responses Delayed separation of the umbilical cord (neutrophils come in and help it die and fall off) Increased circulating neutrophils in the blood → absence of neutrophils at infection site (due to impaired adhesion of marginated pool of leukocytes) Recurrent bacterial infections that lack pus formation (no dead neutrophils) and impaired wound healing. Tx: bone marrow transplant

Pulmonary Embolism

Source: thromboembolism - DVT uncommon - has to be medium and large 10% PEs cause infarctions Must have pre-existing CP compromise Saddle - sudden death Chronic emboli cause pulm HTN Clinical: SOB, hemoptysis, pleuritic chest pain, pleural effusion V/Q mismatch; abnormal perfusion, Clinically silent = lung has dual blood supply (pulmonary and bronchial arteries) and embolus is usually small (self-resolves) Labs: Spiral CT- vascular filling defect in the lung Doppler US- LE Elevated D-dimer Hemorrhagic wedge-shaped infarct Tx: Fibrinolytics Embolectomy

HIV/AIDS clinical stages

Stage 1: Acute infection: •Acute illness occurs in approx. 50% of HIV-infected persons, usually 3-6 weeks after exposure. Typical symptoms are non-specific, and may include fever, night sweats, nausea, myalgia, H/A, sore throat, skin rash, and mild lymph node enlargement. •Represents the initial response of an immunocompetent adult to an HIV infection. •Initially characterized by a high level of virus production, viremia (virus in the blood), and widespread seeding of lymphoid tissue. •An antiviral immune response develops. •Characterized by a self-limited acute illness. •These symptoms last 2-3 weeks and then disappear spontaneously. During this period, some patients develop antibodies to HIV. Stage 2: Asymptomatic infection = Chronic infection: •The phase of asymptomatic infection is of variable duration, lasting from a few months to a few years. The patient is asymptomatic but carries the virus and is infectious. •Corresponds to the middle, or chronic phase. •In this middle phase, there is relative containment of the virus, associated with a period of clinical latency. •Smoldering, low level HIV replication, predominantly in the lymphoid organs, may last for several years. Stage 3: Crisis phase = AIDS: •Approx. 50% of HIV-infected patients develop AIDS within 10 years of initial Diagnosis. •Persistent generalized Lymphadenopathy may develop in patients who are initially asymptomatic. Alternatively, lymphadenopathy may develop early in the course of infection and persist for months or years. •The final or crisis phase is characterized by a breakdown of host defenses, resultant recrudescence (comeback) of viral replication and clinical disease. •The final or crisis phase is characterized by long-lasting fever, fatigue, weight loss, and diarrhea once again. •The CD4+ T-Cell count is markedly reduced. •According to the CDC, any HIV-infected person with a CD4+ T-Cell count of <200/mm3 is considered to have AIDS. Stage IV = multiple comorbidities: •This corresponds to Group IV, those who have other diseases with the viral infection. •The diagnosis of HIV and AIDS is based on clinical findings and laboratory data. The most important laboratory tests are the tests for antibodies to HIV and the lymphocyte counts. •The antibodies to HIV appear at a variable rate, 2 to 10 weeks after infection. The presence of the virus in the body can be confirmed by additional tests, which are often used to avoid false-positive results.

Wells criteria for PE:

Symptoms and Signs Hemoptysis (1 pt) Heart rate > 100/min (1.5 pt) Clinical signs and symptoms of DVT (3 pt) History Previously documented DVT or PE (1.5 pt) Active cancer (1 pt) Bedridden >3 days (1.5 pt) Other PE most likely diagnosis (3 pt) <4 pt = PE unlikely, check D-dimer 4-6 pt = moderate possibility of PE >6 pt = high probability of PE

Embolism (in general)

Thromboembolism - dislodged thrombus Most common from DVT: femoral, iliac, popliteal veins Atherosclerotic embolus - atherosclerotic plaque that dislodges = cholesterol clusters Gas embolism - decompression sickness, Caisson Disease =multifocal ischemic necrosis. Tx: hyperbaric O2 Fat embolism from broken long bone or liposuction - dyspnea, shortly after or after repair Amniotic fluid embolus - enters maternal circulation during labor or delivery - SOB, neuro, DIC, FETAL SQUAMOUS/ KERATIN

Thrombophilia

Thrombophilia is a group of conditions in which there is an increased repeated tendency, often over an extended period of time, for excessive clotting (hypercoagulability). Suspect if recurrent DVT/ DVT at young age Type I = Thrombosis MORE likely: (more severe hypercoagulation disorders) (Antithrombin III, Protein C, Protein S def) Type II = Relatively Mild, more common: Factor V Leiden and G20210A

Disseminated intravascular coagulation (DIC) Tx

Treat underlying cause Transfusing blood products and cryoprecipitate (contains coag factors) as necessary.

Uremia

Uremia = Sign of renal problem. Increased nitrogenous waste products disrupts platelet function. Both adhesion and aggregation are impaired

Venous compression ultrasound

Usually of lower extremity to rule out a deep venous thrombosis (DVT) Echogenic thrombus will be found in a noncompressible venous lumen

Factor V Leiden

Variant of human factor V - Autosomal Dominant - Gene mutation located on chromosome 1 - G → A DNA point mutation (substitute guanine for adenin): Arg506Gln (R506Q) in factor V in an APC cleavage site. Makes it resistant to degradation by APC "Go --> Away protein C as you scream ARG" Most common hereditary or congenital thrombophilia •Found in about 2-8% of Caucasians in N. America and is less common in Hispanics and African-Americans •Women have an increased risk of miscarriage and stillbirth Pathogenesis: Variant factor V causes a hypercoagulability disorder b/c this variant cannot be inactivated by protein C (an anticoagulant which normally inhibits factor Va) •When factor V is not inactivated by protein C, and remains active, it facilitates overproduction of thrombin leading to excess fibrin production and clotting. •The excessive clotting that occurs is restricted to veins (very rarely arteries) causing deep leg vein thrombosis with embolization to the lungs (up to 30% of patients with DVT or P.E. have this condition) Risk for DVT, cerebral vein thrombosis and recurrent pregnancy loss •The thrombosis associated with factor V Leiden appears to be restricted to the venous circulation with only limited controversial evidence for arterial thrombosis or increased risk of myocardial infarction Clinical (APC resistance assay) or genetic •Addition of APC in people with Factor V Leiden effect on PTT = PTT DOES NOT INCREASE. (this is because APC can't inhibit factor V from doing its job in the coagulation cascade - so prothrombin isn't effected)

Deep vein thrombosis (DVT) (can also occur in an artery)

Virchow's triad: Venous stasis + vascular injury + hypercoagulability = high risk Disrupted blood flow: (immobilization, Cardiac dysf., aneurysm) Endothelial wall damage (atherosclerosis, vasculitis, high homocysteine⇒ vit B12/folate def) Hypercoagulable state: estrogen Fibrinolysis def If recurrent/ young age⇒ assume heritable hypercoagulable state Line of Zahn- alternating between clot and RBC + attachment to vessel wall Mainly occur in deep veins below the knee (i.e., anterior and posterior tibial veins) Labs: Elevated D-Dimer diagnostic LE ultrasound Normal PTT/PT/BT Tx: Depends on underlying cause Warfarin or heparin/ other fibrinolytics

Coumarins and VKORC1

Vitamin K epoxide reductase complex 1 (VKORC1) = reduces vitamin K to its active form •Coumarins (e.g. Warfarin) reduce the amount of active prothrombin and factors VII, IX, and X. → inhibit VKORC1, which creates the active form of vitamin K. *Note: do NOT give WARFARIN for people with Protein C def⇒ SKIN NECROSIS They lead to less clotting because they limit the production of the clotting factors by limiting vitamin K activity.

Disseminated intravascular coagulation (DIC) clinical

Widespread microthrombi → ischemia and infarction Widespread bleeding - IV sites, mucosal sites (bleeding from body orifices) Common manifestations of acute DIC include: •Bleeding (64%) •Renal dysfunction (25%) •Hepatic dysfunction (19%) •Respiratory dysfunction (16%) •Thromboembolism (7%) •CNS involvement (2%)

CT angiogram

evaluate possible pulmonary embolus

Uneven endothelium and slow flow (excess clotting)

• Uneven endothelial surfaces in a vessel (due to arteriosclerosis, infection, or trauma) can initiate a clot • Slow blood flow can also initiate a clot due to thrombin or other procoagulants that are always present •Slow flow occurs in the femoral venous flow and such clots can grow and then dislodge and become massive pulmonary emboli.

Antiphospholipid Antibody Syndrome pathogenesis

•Antiphospholipid antibodies (anticardiolipin and anti-apolipoprotein H) react against proteins that bind to phospholipids on plasma membranes •The exact cause is not known, but activation of the coagulation system has been seen, leading to thrombosis and vascular disease. •These autoantibodies bind to apolipoprotein H which in turn inhibits Protein C, predisposing to thrombosis. They also bind Protein S, a cofactor of Protein C, thus decreasing Protein C efficiency. SLE = APA = (INSENSITIVE activated PROTEIN C) (must have SLE)

HIV/AIDS epidemiology

•Clinical AIDS is most often caused by HIV-1, although HIV-2 is an important cause of AIDS in Africa. •The highest prevalence of AIDS has been reported in Africa, where the disease is still spreading at an alarming rate. HIV virus transmission: Homosexual or bisexual men (transfer blood and bodily fluids) IV drug abuse Hemophiliacs Vaginal secretions and sperm (heterosexual contact possible) Maternofetal transmission (transplacental transmission) Minor open wounds (accidental prick with infected needle) Minor incision during operation in a HIV-infected person Hep B risk of seroconversion is 30% after accidental exposure.

AIDS respiratory findings

•In the initial stages, the infections are typically localized to the upper respiratory tract and present as nasal infections or throat infections. •Advanced immunosuppression predisposes the individual to pneumonia, which is often caused by protozoa, such as Pneumocystis carinii, or fungi, like Aspergillus or Candida •Mixed bacterial infections are also common. •A significant number of patients develop pulmonary Tuberculosis and Mycobacterium Avium Complex (MAC)

DiGeorge Syndrome Pathogenesis, clinical, etc.

•NO THYMUS DEVELOPMENT → T cell repertoire not established due to lack of thymic tissue where T cells normally mature. → T cell deficit results in spectrum of immune deficiencies dependent on amount of thymic tissue present. Clinical: •Classic triad conotruncal cardiac anomalies (malformation of infundibulum and great arteries), hypoplastic thymus, and hypocalcemia •Partial DGS = sinopulmonary infections •Complete DGS = severe combined immunodeficiency (SCID) •Severity related to degree of thymic hypoplasia. •Other features presenting outside of infancy and into adulthood = recurrent infections, autoimmunity, developmental delay, psychiatric abnormalities, and chronic inflammatory disease. •Velocardiofacial syndrome: parathyroid hypoplasia; hypocalcemia (tetany); palate, facial, cardiac defects. •Facial features: small head, epicanthal folds, low nasal bridge, small eye openings, short nose, flat midface, thin upper lip, smooth philtrum, underdeveloped jaw. Genetics: 22q11.2 deletion (~90% de novo and ~10% inherited) Autosomal dominant TBX1 haploinsufficiency Epidemiology: CHILDREN Labs: Thymic shadow absent in CXR •↓ PTH and ↓ Ca2+

AIDS tumors

•Patients with AIDS show an increased incidence of all tumors, the most important are lymphomas that occur in the lymph nodes, spleen, liver, and extranodal sites. Primary brain lymphomas are especially common (1000 times more common in patients with AIDS) and are associated with a high mortality. •Histologically, AIDS-related lymphomas do not differ from other lymphomas, and are found to be high-grade, and very malignant. •Kaposi's Sarcoma is a malignant disease involving endothelial cells, seen in the skin, and for unknown reasons, has an especially high prevalence among male homosexuals. It is often multifocal and may involve internal organs as well. Has an association with Human Herpesvirus-8 (HHV-8) Kaposi Sarcoma: •On gross examination, it presents in the form of bluish-red nodules. •Histologically, these nodules are composed of anastomosing vascular spaces filled with blood. •They grow slower than lymphomas, but may cause extensive bleeding, and the mass lesions may compress vital organs and cause death

AIDS neurological findings

•The brain is the only organ that shows HIV-specific changes. In the brain, HIV evokes a microglial response. Microglial nodules with multinucleated giant cells in the subcortical gray matter of the cerebrum are typical of AIDS Encephalopathy. •Overshadowing these changes are lesions caused by opportunistic infections which gives rise to meningitis or encephalitis. •Of the pathogens affecting the brain, the most important are viruses, such as Herpesvirus and Cytomegalovirus (CMV). •Fungi, such as Cryptococcus (most common cause of meningitis in AIDS) Histoplasma and protozoa, such as Toxoplasmosis (periventricular calcifications) also affect the brain. •These infections may destroy part of the brain directly, or by occluding blood vessels and causing ischemic infarcts. •90% of patients demonstrate some form of neurologic involvement at autopsy, and 40-60% have clinically manifest neurologic dysfunction. 1. HIV Aseptic meningitis: occurs within 1-2 weeks of seroconversion in about 10% of cases. Antibodies to HIV can be demonstrated, and the virus can be isolated from the CSF. 2. HIV Subacute Encephalitis: can manifest clinically as a dementia referred to as AIDS-related cognitive motor complex, characterized by mental slowing, memory loss, and mood disturbances (depression). The motor abnormalities include ataxia, bladder and bowel incontinence, and possible seizures. 3. Vacuolar Myelopathy: a disease of the spinal cord, found in 20-30% of AIDS pt's. The histopathology resembles that of Subacute Combined Degeneration, seen in Vitamin B12 deficiency, but levels are normal 4. AIDS-related Myopathy: characterized by inflammation, weakness and pain in the skeletal muscles. •Neurologic disease is common in children with congenital AIDS and manifested clinically by the first year of life, including microcephaly with mental retardation and motor developmental delay with spasticity of the limbs. The most frequent morphologic abnormality is calcification of the blood vessels, and cerebral white matter. Similar opportunistic infections of the CNS also occur, but less often.

AIDS GI tract findings

•The gastrointestinal tract is also often infected, usually by the same pathogens that infect the lungs, (Candida or CMV or Herpes) or by parasites, such as Cryptosporidium or Isospora. Diarrhea and malabsorption of nutrients, caused by these infections, are important factors in the wasting that occurs.

AIDS carcinoma of cervix

•There is an increased incidence in patients with AIDS and is most likely due to a high prevalence of HPV infection in patients with AIDS. This virus is associated with an increased incidence of Squamous Cell Ca. •HPV associated cervical dysplasia is ten times more common in HIV-infected women as compared with unaffected women.

Acquired Thrombophilia and Malignancy

•Thrombosis (DVT with P.E.) is a common complication in cancer patients, up to a four-fold increase, even higher in those undergoing chemo. •Cancer cells can activate the clotting system by their capacity to produce and release procoagulants and inflammatory cytokines with promote thrombosis. •Cancers of the pancreas, lungs, acute promyelocytic leukemia, multiple myeloma and breast cancers can all produce a hypercoagulation