Lecture 29 Flashcards
Define/Describe Leukocytosis V. Leukopenia.
Leukocytosis: Leukocyte count that is higher than normal This occurs as a normal response to: 1. Infection 2. Strenuous Exercise 3. Emotional Changes 4. Temperature 5. Anesthesia 6. Surgery 7. Pregnancy
Leukopenia: Leukocyte count that is lower than normal
Absolute counte is
Define/Describe A. Infectious Mononucleosis; B. Classic v. Non-classic symptoms; C. Etiology and Pathophysiology
A. Infectious Mononucleosis: acute viral infection of B lymphocytes, Self limiting Neoplastic Lymphoproliferation
B. Classic Symptoms (Fever, Malaise, Pharyngitis)
- Lymphadenopathy (swelling of cervical lymph nodes)
- Enlargement of spleen and liver
- If fatal, usually due to ruptured spleen
- Infection is resolved within a few weeks
- Malaise persists for a few months
Non-classic symptoms (these occur in ppl. >30 yrs)
- Peripheral neuropathy
- Guillan Barre syndrome: causes paralysis of the skeletal mm. all the way up to the cervix, affects the mm. of respiration so person needs to be intubated for 2-3 wks until disease stops
- Meningitis/Encephalitis
C. Etiology:
Viral Infection = 85% of infections is Epstein Barr Virus
- Gamma Herpes Virus
- Cytomegalovirus (CMV)
- B lymphocytes has EBV receptors
- Unaffected B lymphocytes produce antibodies against the virus
- Infected B lymphocytes –> plasmoid cells (HUGE activation of Tc cells against virus) - Plasmoid cells overproduces A,M,G Heterophilic antibodies
- These heterophilic antibodies bind to non human RBC’s and cause agglutination
Pathophysiology:
- Spread through close human contact –> SALIVA!!!
* no evidence of aerolized transmission - Incubation: 30-50 days
- Children
For mononucleosis, distinguish the different clinical manifestations in: A. Children , B. Young adults, C. Adults.
A. Children
Describe the “Monospot test” and what substance is it measuring, and why is it there.
The monospot test is looking for the presence of heterophilic antibodies for EBV
5-15% are a fake positive because a lot of viruses produce heterophilic antibodies
Describe Guillan Barre Syndrome and how it relates to Mononucleosis.
Guillan Barre Syndrome is a part of the non-classic symptoms of Mononucleosis. It paralyzes the skeletal mm. from the bottom of the feet all the way to the cervix. It paralyzes mm. of respiration so the person infected needs to be on an intubator until the disease disappears. (usually 2-3 weeks)
Define, Identify, and differentiate the 4 general different types of acute and chronic leukemia.
Describe treatment modalities and relative treatment success.
ALL
ALL = Acute Lymphoblastic Leukemia 80% is from the B cell lymphocytes 15-20% is from the T cell lymphocytes Express ALL or T cell antigens Accounts for 80% leukemia in children, 20% in adults
Philadelphia Chromosome (translocation of chromosomes 9 and 22) the prognosis is worse, more often found in adult ALL
Most = mutation: receptor tyrosine kinases activate mitosis without ligand control
5 year survival rate!
Define, Identify, and differentiate the 4 general different types of acute and chronic leukemia.
Describe treatment modalities and relative treatment success.
AML
AML = Acute Myelocytic Leukemia
Expresses no antigens
Prognosis is poor with AML, worse with philadelphia chromosome
67 is the mean age of diagnosis
Decreased rate of apoptosis
150 mutations, most common is translocation of chromosome 8 and 21
5 year survival rate is 25%
Etiology:
- Radiation
- Down syndrome
- Benzene
- Aplastic anemia
- 1/3 have mutation in tyrosine kinase
Clinical Manifestations:
- Chronic fatigue
- Anemia - panctopenia
- Thrombocytopenia - increased bleeding
- Signs of petechiae and ecchymosis
- Frequent and persistent infections because of leukopenia
- Anorexia
- Splenomegaly and Hepatomegaly, HA, vomiting
- Bone pain- pressure from crowding cancer cells
Define, Identify, and differentiate the 4 general different types of acute and chronic leukemia.
Describe treatment modalities and relative treatment success.
CLL
CLL=Chronic Lymphocytic Leukemia
Neoplastic transformation of lymphoid cells
Predominantly from B cells, some T cells
Generally, CLL pts survive 10 years
More aggressive form has a 3 year survival rate.
Define, Identify, and differentiate the 4 general different types of acute and chronic leukemia.
Describe treatment modalities and relative treatment success.
CML
CML= Chronic Myelogenous Leukemia
Result of injury to DNA of a multipotent myeloid stem cell
95% of CML = Philadelphia chromosome
Describe the common symptoms, pathophysiology and general tx. of Acute leukemias.
*** Classification of Acute Leukemias is dependent upon which stem cells the malignant clonal cells originated from
Acute Leukemia: Abnormal, undifferentiated, immature Lymphocytic Blast cells
Etiology: Cancerous transformation of a blast cell
* a blast cell is primitive undifferentiated blood cell
causative agents-
- Radiation and chemotherapy
- Genetic predisposition
- Exposure to benzene
- Alkylating agents
- Polycythemia Vera
- Chronic Leukemia
- Hodgkins disease
Pathophysiology:
A. Rapid abrupt onset: rapid proliferation of a single mutated progenitor leukoblast cell
B. Crowd out other blood forming cells in the bone marrow
C. Proliferation and Accumulation Disorder (Delayed Apoptosis)
D. Causes panctopenia - all other cellular components of blood are severely reduced ex) anemia, thrombocytopenia
E. Mortality Rate - 7/100,000 persons
F. Untreated = short survival time
Tx:
- Chemotherapy
- Radiation (only to relieve pressure and bone pain)
- Immunotherapy
- Bone marrow transplant
Describe the common symptoms, pathophysiology and general tx. of Chronic leukemias.
Chronic leukemia: advances slowly and insiduously (difficult to treat)
Two main type are CML (DNA damage to multipotent myeloid stem cell) and CLL (neoplastic transformation of lymphoid cells)
State of the art treatment doesn’t:
- Cure the disease
- Prevent blastic formation (acute)
- Does not prolong survival time
Bone marrow transplant after severe chemotherapy
Be able to differentiate between the Acute and Chronic Leukemia in terms of the stem cells involved and how the type of stem cell affects prognosis. Also describe the side effects of the treatments of acute or chronic leukemia.
Acute Leukemia = Blast cells
Chronic Leukemia = for CML (multi-potent myeloid stem cells) and for CLL (B and T cells)
In acute Leukemia has a prognosis of 5 year survival rate.
In chronic Leukemia it has a prognosis of 10 years but if the forms are more aggressive then it is a 3 year survival rate
Acute leukemia treatment has side effects of myelosuppression.
Chronic leukemia treatment doesn’t have major side effects, the treatments just don’t cure the disease.
Describe the Philadelphia Chromosome, delineate which Leukemias have the chromosome and what its presence means relative to Prognosis.
The Philadelphia Chromosome: it is a translocation of chromosome 9 and 22
These Leukemias have the chromosome:
- ALL - acute lymphoblastic leukemia (where the philadelphia chromosome is more often found)
- AML - acute myelocytic leukemia
- CML - chronic myelogenous leukemia
Having this chromosome makes the prognosis for leukemia worse.
Multiple Myeloma
Definition: mature B lymphocyte cancer, aneuploidy, some are tetraploidy
Mature Plasma cell structure and function
Have undergone immunoglobin gene rearrangement
Secrete complete or partial immunoglobin molecules
Etiology:
Originates in Bone Marrow
Governed by cytokines
Accumulates in large masses throughout skeletal system
Translocations of proto-onc genes and some tumor suppressor genes
Pathophysiology:
- unusually large amounts of class 1 immunoglobins (mostly IgG occasionally IgA)
- M proteins - usually ineffective antibodies (damage renal tubular cells)
- Myeloma cells secrete IL- 6 which activate osteoclasts
- Multiple bone lesions and pathological fractures
- Hypercalcemia (fatigue, lethargy, weakness, confusion)
Clinical Manifestations:
- Renal disease and Failure
- Recurrent infections due to suppression of humoral immunity
- Infiltration and destruction of organs, namely bone
Diagnosis: X ray and Bone marrow biopsy assay of immunoglobins
Treatment:
High dose chemotherapy
Radiation
Bone marrow transplant with patients own stem cells x 2 (second after 6-12 months)
Hodgkins lymphoma
Hodgkins Lymphoma: identified by reed sternburg cells, they are a definite diagnosis
Arises from B lymphocytes. They haven’t undergone immunoglobin gene rearrangement and hence don’t secrete antibodies.
Arises from a single cell located in a single lymph node or in a chain of lymph nodes. Usually in the NECK.
Causes oversecretion of cytokines ( IL -1,2,5,6, TNF beta, interferon gamma, and granulocyte colony stimulating growth factor)
The cytokines act in an autocrine and paracrine fashion
Clinical Manifestations:
- Large, not painful mass in the neck. It can spread to axillary, inguinal, retro-peritoneal, and mediastinal nodes. Cause pleural friction rubs and inflammation.
- Fever without infection
- Drenching night sweats
- Itchy skin
Tx: chemo with irradiation and bone marrow transplant
5 year survival for all stages
Non-hodgkins lymphoma
These do not contain reed sternberg cells
Contain 3 categories:
- B cell neoplasms
- NK cell neoplasms
- T cell neoplasms
Transformation of lymphoid tissues –> 67 year transformation
85% from B lymphocytes
15% from T lymphocytes
Viruses it is associated with:
- HIV
- Epstein Barr
- Hep C
- Family history
- Irradiation
Clinical manifestations:
- recurrent infections
- drenching night sweats with fever 38 C and 100.4 F
- weight loss
Tx:
Chemo and radiation
Leukemia
monoclonal malignant disorder of blood forming tissues.
4 types:
- Acute myelocitic leukemia
- Acute lymphoblastic leukemia
- Chronic leuckocytic leukemia
- Chronic myelogenous leukemia
List the different etiologies leading to inherited vs acquired clotting disorders. Describe the
general mechanism for each.
Inherited
Etiology for disorders of coagulation:
defects or deficiencies in one or more of the clotting factors
Hemophilia - usually involves defect in one or more of the clotting factors
It is a sex linked deficiency (found in males)
- women have to be homozygous to get it
In the common pathway, the platelets won’t clot
List the different etiologies leading to inherited vs acquired clotting disorders. Describe the
general mechanism for each.
Acquired clotting disorders
- Liver disease (Hep A,B,C) : involves deficiency in more than one or all of the clotting factors
- Factor VII is the first to decline in liver disease followed by II and X. Liver cell damage is reflected in declines of factor V.
- clotting factors are proteins that are all made in the liver
2. CV disorder: blood flow is too fast or too slow (cellular components settle out of flow and are able to come in contact with the vessel wall
3. Vitamin K deficiency: dietary deficiency. Lipid soluble Vit K is involved in the synthesis and regulation of clotting factors II, VII,, IX, and X as well as the anticoagulant factors proteins C and S.
Source: leafy dark green vegetables and normal flora in the intestines
Poor diet doesn’t lead to Vit K deficiency
PROLONGED WIDESPECTRUM ANTIBIOTICS LEADS TO VIT K DEFICIENCY
- Ca deficiency - low calcium will prolong clotting time proportional to the magnitude of the deficit (HYPOPARATHYROIDISM)
- Vasculitis - damaged healthy endothelial cells stop secreting thrombin inhibiting factors
Define DIC
DIC = Disseminated Intravascular Coagulation
- Abnormal clots form inside the blood vessels.
- These clots use up the blood’s clotting factors, which can lead to massive bleeding in other places.
Describe the various etiologies for DIC and circumstances under which DIC is a risk to a
patient.
note:
intrinsic = surface content extrinsic = tissue damage
- damage to endothelial cells mean they can’t secrete anti-thrombin factors = more clotting
A. Arterial hypotension - shock leading to blood stasis (Leads to intrinsic pathway activation)
B. Hypoxemia - cell damage triggering the release of thromboplastin (TF) = extrinsic pathway activation
*thromboplastin converts prothrombin to thrombin
C. Vascular Obstruction - blood stasis
D. Acidemia - damage to endothelial cells (intrinsic activation)
E. Crushing injuries - leading to TF release (extrinsic)
F. Endotoxin from Gram - species sepsis: endothelial damage (intrinsic)
*MOST COMMON CAUSE OF DIC
G. Severe Inflammation - release of IL-1, TNF, neutrophil, protease
-activate inhibitors of plasminogen activators, XII, thrombin, and others
Thrombus
a clot that is stationary in the blood vessel
Embolus
a clot that is loose and floats around in the blood
These float to other vascular systems with vessels smaller than the embolus. The embolus blocks blood flow to the tissue (if arterial embolus) and the lungs (if venous embolus).
Causes ischemia, hypoxia, tissue injury, death
Treatment:
- IV Heparin - inadvertent hemmorhage
- Oral coumadin - inadvertent hemmorhage
- Streptokinase - digests clots, inadvertent hemmorhage
- Urokinase - digests clots,inadvertent hemmorhage
Arterial thrombus
made mostly of platelet aggregates held together by fibrin strands. can potentially block blood flow to tissues distal to the thrombus.
Venous thrombus
low flow, made primarily of RBC’s, large amounts of fibrin with very few platelets. can potentially become embolus to the lungs.
DVT is potentially life threatening! Need bed rest and anti-coagulation therapy.
Outline the steps during coagulation and fibrinolysis that lead to DIC. (Spend time here, this
isn’t a short answer). Describe the best way to manage DIC.
Coagulation and Fibrinolysis:
- Massive activation of clotting factors
- Unregulated activation of thrombin
- Converts fibrinogen to fibrin
- Induces platelet aggregation
- Leads to fibrinogen depletion
- Leads to platelet depletion
- Activates plasminogen
- High rate of fibrin formation (cross-linked fibrin)–> This then absorbs large quantities of thrombin –> thrombin depletion
- Accelerated Fibrinolysis: Excessive Thrombin and Factor IIX triggers the conversion of plasminogen to plasmin
- plasmin digests clot and produces FDP’s (fibrin degredation products) –> powerful anticoagulant
- leads to plasminogen depletion
- End result is the depletion of clotting factors and plasminogen.
Note: all of the above result in uncontrolled clotting which can be either universal or in specific organs or limbs this results in the depletions of clotting factors and clotting inhibiting factors (thrombin, fibrinogen, plasminogen)
Note: Diffuse and extensive blood clotting obstructs blood flow = ischemia –> hypoxia –> blood blood stasis
- only worsens the activation of clotting and depletes the clotting mechanisms even further
Note: Antithrombin factors required an intact endothelium to facilitate their activity. In the presence of damaged endothelia, anti-thrombin activity is restrained allowing thrombin activity to go unrestrained.
The antithesis of DIC.
- High Thrombin activity causes platelets to be used up in the initial coagulation processes in step one. This further reduces the ability of the blood to form platelet plugs and leading to uncontrolled bleeding.
- High Thrombin activity causes extensive fibrin formation which absorbs thrombin, both processes deplete the blood of both fibrinogen and thrombin leading to an inability to form new clots, contributing to bleeding.
- Depletion of thrombin reduces the ability to activate plasminogen, much of which has already been depleted.
- Extensive fibrinolysis by plasmin leads to the release of FDP’s which act to 1. interfere with Fibrin polymerization
- prevent platelet adherence and aggregation 3. potent anticoagulants which contribute to bleeding
- Administration of NS lactated ringers solution, or whole blood further dilutes blood concentrations of clotting factors, bleeding continues at a high rate.
- The patient bleeds out into the interstitial spaces, thoracic, and abdominal cavities
clinical manifestations of DIC
A. oozing from venipuncutre and arterial line sites
B. development of ecchymosis and hemotomas
C.bleeding from eyes, nose, gums, mucosa
D. pale mottled skin –> cyanosis
E. decreased level of consciousness and confusion
F. Seizures
G. Hemoptysis (coughing up blood)
H. Hypoxia
DIC leads to MODS (multiple organ dysfunction)
Organ most susceptible to micro-vascular thrombosis:
- CV
- Lungs
- CNS
- Kidneys
- Liver
treatment for DIC
- treat underlying cause ex) sepsis give antibiotic therapy
- ** DIC is always a secondary cause
2. restore homeostasis of clotting factors and thrombolytic factors
- restore and or maintain organ viability
- Heparin - controversial but successful with fetuses
- Anti thrombin III (AT III) - inactivates thrombin, useful in treating DIC related to sepsis
- Replacement therapy - THE MOST ACCEPTED TX FOR DIC
- replace components of depleted clotting and thrombolytic system
