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276 Cards in this Set

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History and Epidemiology
When was the first case of HIV originally reported? In what journal was it reported? Where was the report from?
June 1981…MMWR - Morbidity and Mortality Weekly Report…Young men in California
What was the commonality in the young California men that first showed signs of HIV?
They were all homosexual.
What drug was used to treate P. carinii infections?
Pentamadine
What was the first name given to the group of disease affecting homosexuals?
GRIDS - Gay Related Immune Deficiency Syndrome
What opportunisitc infections were originally seen in homosexual men that raised the alarm about HIV/AIDS? Describe them.
Pneumocystic carinii - A rare parasite
Kaposi's Sarcoma - A rare skin disease previously only seen in elderly men in Africa and Southern Europe
Chronic lymphadenopathy - Enlarged lymph nodes
Undifferentiated Non-Hodgkin's Lymphoma - A rare cancer
What was the commonality in the diseases that lead researchers to discover HIV/AIDS?
They were all only seen in humans with severly impaired immune systems.
What is the time called when a patient has a depressed immune system, but does not show symptoms?
Asymptomatic or latency period.
What demographic other than homosexuals began showing signs of HIV/AIDS in the early 1980s?
Patients that had been treated with blood or blood products, including hemophiliacs, blood-transfusion recipients, and intravenous drug users.
What was the HIV virus originally called? Who discovered it? Who won the Nobel Prize for discovering it?
Human T-Lymphotrophic Virus Type III
Luc Montagnier and Robert Gallo
Montagnier won the Nobel
What child served as the face for AIDS and HIV patients? How did he contract HIV/AIDS?
Ryan White…Blood products used to treat his hemophilia
What was enacted after Ryan White's death? What did it do?
CARE (Comprehensive AIDS Resources Emergency) Act…Improved availability of funding for treatment of low-income, uninsured, and underinsured AIDS patients.
List all of the ways that HIV is transmitted.
Sexual contact
Contaminated blood used clinically
Sharing of needles for intravenous drug use
Mother to fetus during childbirth
What are the body products that HIV is found in?
Blood…Semen…Cervical secretions…Saliva…Feces
At what rate is HIV passed from mother to fetus if not treated?
30% of births
What is the current demographic that is newly infected with HIV?
Blacks and hispanics are disproportionately infected with HIV.
Origin and Virology
In whose tissue was the first HIV found?
Frederic Brugiere
What are the three theories about the origin of HIV?
Virus became more virulent
Virus was introduced from an isolated population
Zoonotic transfer from another organism to humans
Which theory about the origin of HIV is considered the most likely?
A zoonotic transfer of Simian Immunodeficiency Virus (SIV) is thought to be the cause of HIV-1 and HIV-2.
What type of SIV is thought to cause HIV-1? HIV-2?
SIV chimapanzee
SIV mangabey
What is the most predominate HIV-1 subtype in the US?
HIV-1B
What are the three groups used to classify HIV-1?
M (main)
N (non-M, non-O)
O (outlier)
When was the earliest case of HIV seen? Where?
Found in the preserved blood of a male that lived in the Congo in 1959.
What gensus and family is HIV a member of?
Lentivirius
Retroviridae
How are Lentiviruses transmitted?
Single stranded, positive-sense, enveloped RNA viruses
How is HIV RNA incorportated into the host DNA?
Reverse transcriptase
Describe the structure of HIV outside of the host?
An outer shell called the envelope that is made from proteins and lipids with an inner core of proteins surroudned by RNA strands.
What are the proteins that make up the outer core? How many of these proteins are there?
gp120 and gp41 make up the external spikes seen on HIV.
They form the 72 spikes seen on the envelope
What are the proteins that make up the inner core?
4 nucleocapsid proteins formed by the proteolytic cleavage of the p53 gag precursor protein.
There are two copies of the single-stranded HIV-1 genomic RNA and then proteins that code for reverse transcriptase, protease, and integrase.
What is the HIV-1 gene that encodes the structural elements of the virus?
Gag gene
What is the HIV-1 gene that encodes reverse transcriptase and integrase?
Pol gene
What is the HIV-1 gene that encodes the precursor to gp120 and gp41?
Env gene
What does the Tat gene do in HIV-1?
Helps HIV reproduce by binding to and phosphorylating cellular factors, allowing for transcription of the HIV DNA.
What does the Rev gene do in HIV-1?
"Regluator of Virion" RNA is exported from the nucleus before it can be spliced so that the structural proteins and RNA genome can be produced.
What does the Vpr gene do in HIV-1?
"Viral Protein R" regulates nuclear import of the HIV-1 pre-integration complex and is required for virus replication in cells such as macrophages.
What does the Nef gene do in HIV-1?
"Negative Regulatory Factor" ensures T cell activation and the establishment of a persistent state of infection.
What does the Vif gene do in HIV-1?
"Viral Infectivity Factor" inhibits APOBEC3G which prevents hyper-mutation of the viral genome which would cause it to be inactive.
What does the Vpu gene do in HIV-1?
"Viral Protein U" involved in viral budding, enhancing the release of the virion from the cell.
What is the life cycle of HIV-1?
Attachment/Fusion
Viral RNA enters cytoplasm
Reverse Transcriptase and DNA Synthesis
Transport to nucleus
Integration in host DNA
Viral Transcription
Viral Protein Synthesis
Assembly of Virus
Release of Virus
Pathogenesis
What are the types of infections that occur as a result of AIDS?
Protozoa
Mycobacteria
Herpes Viruses
Fungi
What are the neoplams that occur as a result of AIDS?
Kaposi's Sarcoma
B-Cell Lymphoma
Squamous Cell Cancer
What is ARC?
AIDS-related complex
Defined as symptomatic HIV-infected persons who have suffered weight loss, fatigue, unexplained fever, or low-grade opportunisitc infections.
What are the stages of HIV-1? Describe them.
Stage 1 - HIV infection is asympotamtic and not categorized as AIDS.
Stage 2 - Minor mucocutaneous manifestations and recurrent upper respiratory tract infections.
Stage 3 - unexplained chronic dairrhea for longer than a month, severe bacterial infections and pulmonary tuberculosis.
Stage 4 - toxoplasmosis of the brain, pneumocystis pneumonia, candidiasis of the esophagus, trachea, bronchi or lungs, NHL, KS
What are the ways in which HIV is different from other epidemic pathogens?
Directly attacks the immune system.
Involves thymus incorporation into the cellular genome.
Established a chrnoic infection before becoming pathogenic.
Involves an agent that frequently changes/mutates.
Recruits other cells by direct infection or cell-cell contact.
What are the in vivo targets of HIV?
CD4+ lymphocytes
macrophage-monocytes
neuronal cells
fibroblasts
astrocytes
follicular dendritic cells
what is the primary location of viral accumulation before it is detectable in blood?
Within infected cells and bound to FDCs.
How does HIV kill cells?
Displaying gp120 on the cell surface causing healthy CD4+ T-cells to merge forming a synctium. A normal cellular immune response occurs by natural killer cells and antibody attack with CD8+ cytotoxic T-cells.
How many virions are produced per day in a symptomatic patient?
1 x 10^9
What are the patterns of HIV disease progression?
Typical - median survival of 10 years, symptoms within 3-6 weeks of infection which disappear within 9-12 weeks followed by latent period for 8-10 years.
Rapid Progressors - rapid course of 3-4 years, defective immune response with antibody levels low to absent and inadequate production of interleukin-2, very high viral load.
Long Term Nonprogressors - immune function is conserved with normal CD4+ and CD8+ T-lymphocyte counts; viral loads and replication levels are 4 to 20x lower than typical progressors
What is the effect of HIV on tissues and organ systems?
Infection suppresses hematopoiesis
Infection of the CNS and GI tract lead to physiological distubances
What are cofactors that can increase HIV pathogenesis?
Alcohol, smoing, drugs, stress and STD infection.
What are the three clinical stages of HIV?
Early period with high viral load
Persistant period with lower threshold due to immune response
Symptomatic period with increased viral production.
What is long term HIV survival dependent on?
CD8+ and interleukin-2 levels
How many HIV particles are produced daily in an untreated patient?
50-500 billion
How effective must antiviral therapies be to extinguish the infection?
>90% effective
What is the test used for the initial screening for HIV?
ELISA - Enzyme Linked ImmunoSorbent Assay
How does ELISA test for HIV?
Uses an antigen prepared with whole virus from tissue culture or HIV antigens from recombinant DNA technology.
What does the well in an ELISA test look like if the patient is HIV+?
It will be colored.
What is the secondary test for HIV status? How does it work?
The immunoblot (Western blot) is used. The patient's serum is layered on to the blotted antigens.
Other than Western blot and ELISA, what other tests are used to screen for HIV?
PCR is used to detect DNA and RNA HIV gene sequences, but false-positives are a major concern.
What is the normal range for CD4+ cells?
500-1500 cells/mL
At a CD4+ count of less than 500, what infections are seen?
Bacterial pneumonia and M. tuberculosis.
At a CD4+ count of less than 300, what infections are seen?
Kaposi's Sarcoma
At a CD4+ count of less than 200 what infections are seen?
Pneumocystis pneumonia, crytococcus neoformans, Non-Hodgkin's Lymphoma
At a CD4+ count of less than 50 what infections are seen?
Mycobacterium avium comples, Apergillus, Candida, Cytomegalovirus
What is the common opportunistic infection that attacks the lungs?
Mycobacterium tuberculosis.
What opportunisitic infections is seen in more than 80% of AIDS patients?
Pneumocystis penumonia caused by Pneumocystis jirovecii (carinii)
What infection is seen in HIV patients that are "wasting"?
Mycobacterium avium comple (MAC)
What are the hematological impacts of HIV?
Impaired hematopoiesis and immune-mediate cytopenias including anemia, thrombocytopenia, and neutropenia.
How is HIV involved in B-cell lymphoma?
HIV is not directly involved in B-cell lymphoma. It plays an indirect role by weakening the immune syste.
What causes Kaposi's Sarcoma?
Exposure to herpesvirus-8 (HHV-8)
Therapy
What is different about the genetics of HIV versus other viruses?
It's incredibly high rate of genetic variability.
What aspect of the brain makes it difficult for pharmaceuticals to attach HIV?
The blood-brain barrier prevents the drugs from killing the virus.
What can be done to reduce the risk of infection immediately after exposure?
Antiretroviral therapy give as "post-exposure prophylaxis" can reduce the risk of seroconversion.
What is the current HIV treatment in the US?
HAART - highly active antiretroviral therapy
What is the major clinical indicator of immunocompetence?
The CD4+ T-cell count
What is the recommended time to start antiretroviral treatment?
It should be started in all patients with a history of an AIDS-defining illness or severe symptoms of HIV infection regardless of CD4+ T-cell count.
It is also recommended for asymptomatic patients with a CD4+ T-cell count of less than 200 cells/mL.
What are the considerations of starting ART in asymptomatic patients?
If the CD4+ T-cell count is > 350 and the plamsa HIV load is > 100,000 copies/mL, treatment is often defered.
In patients with CD4+ >350 cells/mL and HIV RNA <100,000 copies/mL, should be deferred.
What was the first anti-HIV drug?
AZT (azidothymidine) which was found in the 1980s.
What are the four classes of antiretrovial drugs?
Nucleoside/nucleotide reverse transcriptase inhibitors (NRTI)
Non-nucleoside reverse transcriptase inhibitors (NNRTI)
Protease inhibitors (PI)
Entry inhibitors (EI)
What are the two different combinations of drugs used for combination therapy?
NNRTI Based (1 NNRTI + 2 NRTI)
PI Based (1-2 PI + 2 NRTI)
What is the preferred combination drug therapy?
PI Based (1-2 PI + 2 NRTI)
What is the disease progression of HIV in children? How does this impact treatment?
It is more rapid and thus the treatment must also be more aggressive.
Describe NRTIs. NNRTIs.
Both are inhibitors that stop HIV from multiplying by blocking the reverse transcriptase enzyme.
Describe PIs.
Block the protease enzyme which helps assemble the mature virion.
How does AZT function?
It is an NRTI that is incorporated into the growing chain of viral DNA instead of a normal thymidine residue. This "mistake" cannot be repaired by the virus and the DNA synthesis comes to a halt.
What is the gene product that is impacted by a PIs inhibition of protease?
The Gag-Pol precursor.
What are the major effects of HAART?
Reversal in the rate of decline of CD4+ cells
Reduction in opportunistic infections
Improvement in CNS function
Improvement in survival.
What are the side effects of HAART?
GI intolerance
Nausea
Vomiting
Diarrhea
Paresthesia
Lipodystrophy
Formation of a "Buffalo Hump"
What are the downsides of HAART?
Discontinuation of HAART leads to rapid return of viremia
It is expensive
It has toxic side-effects with long term use.
Compliance is very difficult.
To what must HIV bind to induce infection?
It must attach the the CD4+ receptor, then it must interact with coreceptors which brings the virion closer to the cell and allows for fusion to occur.
What are the coreceptors to which HIV binds?
Fusin (CXCR4) and CCR5
What type of receptors are the coreceptors?
Chemokine receptors
What are the ligands for CCR5?
RANTES, MIP-1α and MIP-1β
Fusin (CXCR4) coreceptors are found on what type of cells?
T-cell lymphocytes
CCR5 coreceptors are found on what type of cells?
Monocytes and macrophages
How do entry inhibitors function?
They attach themselves to proteins on the surface of CD4+ cells, preventing the HIV virus from binding to the cell.
Transfusion and Hepatitis
Into what components is whole blood collected in the US separated?
Red cells
Platelets
Plasma
How is whole blood separated?
Fractionation
How much of each component is provided by one unit of whole blood?
Red cells - one unit
Platelets - one unit
Cryoprecipitate - one unit
Platelet - one unit
Cryoprecipitate-Poor Plasma - one unit
Who specifies the donor medical requirements?
the FDA.
What is the minimum weight for a standard blood donation?
110 lbs.
What is the maximum blood pressure for blood donation?
90/180
What is the minimum hemoglobin concentration for blood donation?
12.5 g/dL
What is the normal amount of blood collected in a donation? What percentage of the donor's total blood is this?
~450mL
Up to 13%
How long does it take blood volume to return to normal?
72 hours
What are the antibodies found in a patient with Type A blood? Type B? Type AB? Type O?
Anti-B
Anti-A
None
Anti-A and Anti-B
What is the inheritence of ABO genes?
Codominant
What is the blood type of universal donors? Universal recipients?
Type O
Type AB
What is hepatitis?
Inflammation of the liver.
What are the symptoms of hepatitis?
Jaundice, fatigue, abdominal pain, loss of appetite, etc.
Is hepatitis viral or bacterial?
Viral
Which viruses can cause acute viral hepatitis?
All (A, B, C, D, and E)
Which hepatitis viruses can cause chronic hepatitis?
B, C, and D
What is the impact of chronic hepatitis?
Inflammation of the liver with the eventual replacement of liver cells with fibrotic tissue resulting in cirrhosis.
What is the virus that causes Hepatitis A? How is it transmitted?
Picornvirus
Orofecal route, close personal contact, contaminated food
What is the virus that causes Hepatitis B? How is it transmitted?
Hepadnavirus
Blood, tattoos, sexually, mother to child via breast milk
What is the virus that causes Hepatitis C? How is it transmitted?
Flavivirus
Contact with blood or across placenta
What is the treatment for HBV?
Alpha-interferon, adefovir, and lamivudine
What is the treatment for HCV?
No vaccine is available.
Can be treated by a combination of interferon and ribavirin (an antiviral) if detected early.
Primary Hemostasis
What is the purpose of the hemostatic system?
To ensure blood is confined to the circulatory system and flows through it freely.
What is a hemorrhage?
An inherited or acquired disorder of the hemostatic machinery that causes abnormal bleeding.
What are the mechanisms by which bleeding is arrested?
Vasoconstriction - the narrowing of blood vessels
Hemostatic Plug Formation - platelets and fibrin interact to prevent RBCs and WBCs from leaving the vessel.
What are the distinct systems that are part of the hemostatic mechanism?
Vascular system
Blood coagulation system
Blood platelets
Fibrinolytic system
Inhibitors of these systems
What are the three subsystems of the circulatory system?
Systemic circulation
Pulmonary circulation
Portal blood systems
Describe systemic circulation.
Delivery of oxygenated arterial blood from the left ventricle to the body tissues and retun of deoxygenated venous blood to the right artrium.
Describe pulmonary circulation.
Deliver of deoxygenated blood from the right ventricle to the lunds and the return of the oxygenated blood to the left atrium.
Describe the portal blood systems.
They act as venous conduits that transport substances such as nutrients and hormones from various sites.
What is the largest portal system?
The hepatic portal system connects the intestine and the spleen to the hepatic sinusoids. These sinusoids drain into the hepatic veins and from there into the vena cava that carries blood directly to the heart.
What features of the blood vessels aid hemostasis?
They are designed for the smooth movement of blood from the heart to the tissues and back.
They are considered to have an anticoagulent surface that prevents clots from forming by keeping blood moving.
What is the function of platelets?
Helps to maintain the integrity of the vessel lining. They plug ruptures in the circulatory vessels.
What are plasma proteins?
Soluble circulating blood proteins that help maintain hemostasis.
What maintains primary hemostasis?
The vessel wall (endothelial cells) and platelets.
What maintains secondary hemostasis?
Proteins and other cofactors provide coagulation.
What are the primary differences between arteries and veins?
Arteries are more muscular than veins.
Veins contain valves that prevent blood from being pulled down by gravity.
What is the effect of prostacyclin on vascular endothelium?
Inhibits platelet aggregation and causes vasodilation.
What is the effect of thromboxane A2 on vascular endothelium?
Causes muscular arteries to contract. Produced by platelets
What is the effect of ELAMs, ICAMs on vascular endothelium?
Cytokines induce synthesis of materials that promote leukocyte adhesion.
What is the effect of von Willebrand factor on vascular endothelium?
Promotes platelets-collagen adhesion to exposed sub-endothelium.
What is the effect of TFPI (tissue factor pathway inhibitor) on vascular endothelium?
It is an anticoagulent that inhibits the coagulation extrinsic pathway.
What is the effect of thrombomodulin on vascular endothelium?
It is an anticoagulent that inhibits coagulation by activating the protein C system.
What is the effect of TPA (tissue plasminogen activator) on vascular endothelium?
It is an anticoagulent that inhibits coagulation by activating fibrinolysis. It is used in clot busting drugs that are given to heart attack victims.
What is the effect of heparan sulfate proteoglycans on vascular endothelium?
It is an anticoagulent that inhibits coagulation by activating antithrombin.
What is the effect of tissue factor on vascular endothelium?
It is a procoagulant that’s expression is induced by inflammatory cytokines (IL-1 and TNF).
What are the prothrombic components of the vessel wall?
vWF, collagens, fibronectin, TF
What causes the coagulation cascade to occur?
Thrombin
What are blood platelets formed from? What is their size in relation to other blood cells.
The cytoplams of bone marrow megakaryocytes. They are the smallest.
What is the normal blood platelet count?
150-400 x 10^9/L
What is unique about the structure of platelets?
They are anucleated, but have a complext internal structure that is completely related to the specific hemostatic functions of the platelet.
What are the two major types of intracellular granules in blood platelets?
α-granules and dense granules
What do α-granules contain?
Coagulation factors (fibrinogen, vWF, factors V and VIII) and platelet-derived growth factor.
What do dense granules contain?
ADP, ATP, and serotonin
What causes α-granules and dense granules to release their contents?
Activation of platelets.
What are the four properties of platelets during primary hemostasis?
Adhesion to a surface
Shape change
Release of granule content
Aggregation
What occurs within a few seconds of injury?
Platelets adhere to collagen fibrils in vascular subendothelium via a specific platelet collagen receptor.
What is the effect of aspirin on platelets?
It irreversibly inactivates the enzyme cyclooxygenase (COX-1 and COX-2) which prevents the production of thromboxane A2. This inhibits aggregation for the life-time of the platelet.
How does aspirin's effect differ between endothelial cells and platelets?
Aspirin destryos COX-1 and 2 in both cells, but the endothelial cell just makes more. The platelet can't do this as it doesn’t have a nucleus or the required machinery.
Secondary Hemostasis
What is the effect of blood clotting improperly in a vessel?
Ischemia (deficiency of blood to tissues)
Necrosis (death of a tissue)
What are the broad ways in which hemostasis is regulated?
It is only active when necessary and it is terminated as soon as a hemorrhage is under control.
Who first discovered fibrin? What was his hypothesis about the role of fibrin in clotting?
Plato
He hypothesized that it formed a clot when it left the body and cooled.
What are the two traditional pathways by which coagulation factors are divided?
Intrinsic cascade - factor XII contacts thrombogenic surface
Extrinsic cascade - blood is exposed to extravascular (subendothelial) tissue factor (TF)
What is the end result of coagulation?
Soluble fibrinogen is converted into insoluble polymerized fibrin which is then catalyzed to thrombin.
What is the most important step in coagulation?
The generation of thrombin as it provides maximal stabilization.
Describe the coagulation cascade.
Coagulation is initiated by endothelial injury which releases tissue factor (TF)
TF combines with factor VIIa to from a complex that activated factor IX and X
Factor IXa and factor VIIIa further activates factor X
Factor Xa and Va catalyzes conversion of prothrombin to thrombin
Thrombin converst fibrinogen to fibrin
Where are coagulation factors synthesized?
The liver with vWF as an exception which comes from the endothelial cells and megakaryocytes.
What type of proteins are coagulation factors?
Serine protease plasma proteins
What are zymogens?
Inactive plasma proteins which are cleaved by a specific enzyme and become active enzymes.
What does it mean that coagulation factors are serine proteases?
Their active sites contain a serine amino acid.
What are the four types of coagulation factors?
Zymogens
Cofactors
Non-Protein Cofactors
Fibrinogen and Factor XIII
What is the role of a cofactor?
They help accelerate the coagulation reactions and must be activated by proteases.
What is the purpose of thrombin?
It converts fibrinogen to fibrin.
What is the final component of coagulation?
Factor XIII, a transglutaminase that cross-links and further stabilizes the fibring strands. It is the covalent glue between fibrin strands.
What are the zymogens?
Vitamin K Dependent - II, VII, IX, X
Vitamin K Independent - Xi, XII, XIII
What are the cofactors?
V, VIII, TF, vWF
What are the non-protein cofactors?
Calcium and Phospholipid surfaces
What occurs to thrombin?
It is cross-linked by activated factor XIII
What happens in fibrinolysis is too high?
Hemorrhage takes place
What happens if coagulation is too high?
Thrombosis occurs
What solution is used as a anticoagulant?
Citrate
It stops clotting by binding to calcium. The ratio of blood to citrate is 9:1
What are the intrinsic proteins?
Prekallikrein
Kininogens
XII
XI
IX
VIII
What are the extrinsic proteins?
TF (III)
VII
What are the common pathway proteins?
X
V
III(prothrombin)
I(fibrinogen)
What does the thrombin clot time test (TCT) analyze? What are the components of this test?
Measures the conversion of fibrinogen to polymerized fibrin.
Test plasma and thrombin are added and the time to form a fibrin clot is measured.
What does it mean if the TCT test is failed?
There is not enough fibrinogen in the patient's plasma. Potentially liver disease.
What does the prothrombin time (PT) test analyze? What are the components of this test?
Tests the extrinsic and the common pathways. Test plasma + complete thromboplastin (source of TF and lipid) + CaCl2 with the time required to form a clot being measured.
What does it mean if the PT test is failed?
Patient has a deficiency of fibrinogen, prothrombi, V, X, or VII. Indicates a vitamin K deficiency, warfarin poisoning, liver disease, or DIC.
What does the activated partial thromboplastin time (APTT) test analyze? What are the components of this test?
Tests the intrinsic and common pathways.
Test plasma + partial thromboplastin (lipid only) + particulate substance (Schmutz) + CaCl2
What does it mean if the APTT test is failed?
The patient has a deficiency of fibrinogen, prothrombin, V, X, VIII, IX, XI, or XII.
What does an APTT mixing study show?
If equal volumes of patient plasma and normal plasma are mixed and the APTT test is repeated, and the time returns to normal, this indicates that a blood coagulation factor is deficient. It does not show which factor is deficient. If the mixing does not correct the APTT, there is a factor inhibitor in the patient's blood.
What technique has replaced the bleeding time test?
Platelet Function Analysis
What does Platelet Function Analysis (PFA) show over BT?
Detects vWF-dependent platelet dysfunction under high-shear stress
Platelet Disorders
What are petechiae?
Pin point hemorrhages caused by increased vascular permeability of failure of platelets in capillaries.
What are purpura?
Confluent patches of petechiae.
What are ecchymoses?
Large amounts of extravasated blood under the skin. Also called a bruise.
What are hematomas?
A large ecchymoses that involves subcutaneous tissue or muscle
What are hemarthrosis?
Hemorrhage into a joint.
How does vWF function?
Bridges the platelet receptor glycoprotein Ib (GPIb) to collagen in the subendothelium.
What is released by granules in platelets?
ADP and TxA2 which recruit other platelets to the site of injury.
What is released by endothelial cells to inhibit further platelet aggregation?
Prostacyclin (PGI2)
Nitric oxide (NO)
What is the lifetime of a platelet?
7-10 days in the blood.
What regulates the production rate of platelets?
Thrombopoietin
What are the symptoms of platelet hypofunction?
Epistaxis, gum bleeding, bruising, heave menses, petechiae.
Hematomas or hemarthroses are not seen.
What are the three types of defects seen in platelet disorders?
Adhesion
Secretion
Aggregation
Why do adhesion disorders occur?
von Willebrand's Disease - abnormality or absence of plasma cofactor required for platelet adhesion
Bernard-Soulier Syndrome - defect in the platelet
Ehlers-Danlos Syndrome - abnormality of the subendothelial connective tissue
When do symptoms of thrombocytopenia occur? When is it life threatening?
When platelet count is <50K/µL
<20K/µL.
What is the opposite of thrombocytopenia?
thrombocytosis or thrombocythemia
What are the major causes of thrombocytopenia?
Decreased platelet production
Abnormal platelet distribution
Increased platelet destruction
What can cause defects in bone marrow causing defective platelets to be formed?
Injury caused by drugs, radiation, or chemotherapy
Invasion caused by leukemia or solid tumor
Ineffective metabolism (B12 or folate deficiency)
Where do a large number of platelets pool?
In the spleen (1/3 are found here).
What can cause accelerated destruction of platelets?
DIC
Immune thrombocytopenic purpura (ITP) or thromboti thombocytiopenic purpura (TTP) from autoantibodies
How is DIC diagnosed?
Eleveated PT
Low platelets
Low/falling fibrinogen
Elevated fibrin degradation
What is the typical type of antibody against platelets? What surface proteins does it recognize? Where is it produced?
IgG
Glycoprotein, I, IIb, and IIIa
In the spleen
Where is acute ITP seen? What are the symptoms?
Children or young adults
Mild to moderate bleeding
Where is chronic ITP seen? What are the symptoms?
Adults
Typically asymptomatic at presentation, bleeding is less prominent, seen mostly in females (3:1)
What is the treatment for ITP?
Corticosteroids
Splenectomy
What is thombotic thrombocytopenic purpura (TTP)?
Rare, life-threatening disorder caused by platelet microthrombi in small vessels causing organ dysfunction.
What is the TTP "pentad"?
Thrombocytopenia
Microangiopathic hemolytic anemia
Fever
Renal dysfunction
Neurologic abnormalities
Schistocytes in blood smear
What is a schistocyte?
An irregularly shaped RBC fragment cause by trauma.
What is the cause of TTP?
Deficiency or inhibition of ADAMSTS13 which cleaves vWF into smaller fragments.
What is the acute form of TTP like?
Fulminant (intense and severe and quick onset)
How is accute TTP treated?
Plasma exchange (plasmapheresis) or cryoprecipitate-poor plasma that is depleated of vWF. Platelets ARE NOT transfused.
Hemophilias, vWF Disease, and Hemorrhage
What coagulation factor disorders are x-linked recessive? What sex are they only seen in?
Factors VIII and IX
Males
Why type of bleeding occurs in patients with congenital plasma coagulation defects?
Hemarthrosis
What factor is deficienct in hemophilia A?
Factor VIII
What factor is deficienct in hemophilia B?
Factor IX
What coagulation factor is complexed with vWF? Where is it synthesized?
Factor VIII
Formed in the liver
What level of factor VIII is required for normal hemostasis? What level causes mild Hemophilia A? Moderate? Severe?
25%
<25% but >5%
>1% but <5%
<1%
What is the level of factor VIII seen in most Hemopilia A?
<5%
What is the treatment for Hemophilia A?
Clotting factor replacement.
What coagulation factor is missing in Hemophilia B?
Factor IX
What is the general treatment for Hemophilia A or B?
Avoid the use of aspirin-containing drugs
Plasma products with factor VIII or IX
How does von Willebrand's Disease differ from Hemophilia?
Mucocutaneous hemorrhage rather than hemoarthroses
Autosomal dominant inheritance
Prolonged BT unlike normal BT in Hemophilia patients
What are the clinical symptoms of vWD?
Primary and secondary hemostatic defects.
What is the treatment of vWD?
Plasma concentrates with vWF or DDAVP which causes the release of vWF stored in endothelium.
What are the possible sources of acquired coagulation disorders?
Vitamin K deficiency
Liver disease
DIC
What are the three major causes of vitamin K deficiency?
Inadequate intake
Intestinal malabsorption
Loss of storage sites due to hepatic disease
What are the test results for someone with a vitamin K deficiency?
Prolonged PT and normal APTT initially as factor VII drops first and then APTT lengthening as the other factors fall as well.
What is the treatment for vitamin K deficiency?
10mg parenterally administered.
What did Virchow think caused thrombosis?
Abnormalities in the vessel wall, blood flow, and properties of the blood.
What changes in blood constituents would cause thombosis? Where would these thromboses occur?
Antithrombin deficiency; acquired hypercoagulability
Veins
What changes in blood vessels would cause thombosis? Where would these thromboses occur?
Endothelial injury secondary to atherosclerosis, trauma, or chromic inflammation
Arteries and veins
What changes in blood flow would cause thombosis? Where would these thromboses occur?
Stasis and turbulence
Veins
What does Facto Vleiden cause?
Increased prothrombin synthesis
What is the most common cause of venous thrombosis?
Stasis
What are the objectives of treating venous thromboses?
Prevent extension of the thrombus
Prevent it from embolizing
Induce accelerated fibrinolysis
What are the objectives of treating arterial thromboses?
Prevent extension and total coronary occlusion
Prevent acute myocardial infarction
Idea is to reopen the artery as quick as possible.
How is a venous thrombosis treated?
Heparin
Warfarin
Fibrinolytic enzymes
Leg compression
How does heparin work?
It binds to antithrombin and converts it to a protease inhibitor of thrombin.
What type of molecule is heparin?
Heterodispersed polysaccharide
How does warfarin work?
Inhibits vitamin K epoxide reductase and thus all vitamin K-dependent coagulent proteins
How does fibrinolytic therapy work?
Plasminogen activators are infused
What is the standard treatmetn for acute venous thrombosis and pulmonary embolism?
Heparin followed by warfarin.
What is the standard treatment for coronary thrombosis?
Heparin, LMWH, and warfarin along with anti-platelet compounds and fibrinolytics
Atherosclerosis
What is the chief characteristic of atherosclerosis?
Plaques called atheromas protrude into the lumen.
What happens with coronary atherosclerosis?
Ischemic heart disease occurs. This can be complicated by thrombosis and mycardial infarction.
What leads to thrombosis and the start of an accute event in atherosclerosis?
The rupture of a plaque.
What causes Peripheral Artery Diease?
Atheromas in the extremities.
What are the two main types of stroke?
Ischemic stroke - blockage of a blood vessel
Hemorrhagic stroke - bleeding in the brain
What is the most common type of stroke?
Ischemic stroke
What is a complicated lesion?
One the ruptures and begins to have platelets stick to it.
What is the relationship between AS and LDL?
Direction relationship
What is the relationship between AS and HDL?
Inverse relationship
What are the ABCDEs of Coronary Heart Disease?
Aspirin
Beta Blockers
Cholesterol lowering drugs
Don't smoke
Exercise
What is an ACE inhibitor?
Angiotensin-converting enzyme treates hypertension and congestive heart failure.
What is a statin used for?
Lowering the blood levels of LDL.
How do statins work?
Inhibits (HMG-CoA) reductase which prevents the synthesis of cholesterol.
What are the risk factors of metabolic syndrome?
Central obesity
Atherogenic dyslipidemia
Insulin resistance
Prothrombic state
High BP
Proinflammatory state