Coagulation

1. vessel spasm
2. formation of platelet plug
3. blood clot formation (development of insuable fibrin)
4. clot retraction and fibrous tissue growth (permanent repair of vessel injury)
5. clot dissolution

Thromboxane A2 (TXA2)

released from platelets, plays a primary role in the recruitment and activation of more platelets

life-span:  7-9 days

Normal counts:  150,000 - 400,000 /cumm

myeloid progenitor

↓

megakaryoblast

↓

megakaryocyte

↓

platelets

thrombopoietin stimulates megakaryocytes in the bone marrow → plateles formed (fragments of megakaryocyte) → released into circulation and processed in the spleen for ~8hrs →  released into circulation

von Willebrand factor (vWF)

vWF is found in the endothelial cells of blood vessels and circulates attached to Factor VIII

trauma to the vessel wall →  vessel wall loses (-) charge →

(-) charged platelets adhere to the (+) charged vessel wall and become activated (expose surface receptors) →

bind to vWF in the exposed matrix (collagen)

ADP

TXA2, thrombin (platelet activating factors)

involved in aggregation of platelets → meshwork formation

Factors II, VII, IX, X

2+7 = 9 + 1 = 10

Name the following Factors:

Factor I

Factor II

Factor III

Factor IV

Factor IX

Factor XIII

Name the following Factors:

Factor I         Fibrinogen

Factor II       Prothrombin

Factor III     Tissue thromboplastin

Factor IV       Calcium

Factor IX       Christmas Factor

Factor XIII   Fibrin stabilizing factor

antithrombin II

heparin

alpha2 macroglobin

Protein C

stages of blood clot formation

Stage 1:  formation of prothromin activator (release/generation of thromboplastin) via the intrinsic or extrinsic pathways

Stage 2:  conversion of prothrombin → thrombin

Stage 3:  conversion of fibrinogen → fibrin

conversion of prothrombin → thrombin occurs at what stage of blood clotting (1-3)?

Stage 2:  conversion of prothrombin → thrombin

the __________ pathway is activated by tissue damage and involves tissue/thromboplastin factor (TF) and factor VII.

what blood test is used to assess this pathway?

the extrinsic pathway is activated by tissue damage and involves tissue/thromoplastin factor (TF) and factor VII.

Prothromin time (PT) is used to assess this pathway

the extrinsic pathway is activated by the release of tissue factor from damaged tissue cells. Tissue factor (TF) activates Factor VII, which then converges with the intrinsic pathway at factor X

the __________ pathway is activated by damage to the blood or contact with collagen within the vessel wall and involves factors XII, XI, IX, VIII

what blood test is used to assess this pathway?

the intrinsic pathway is activated by damage to the blood or inner blood vessel and involves factors VIII, IX, XI, XII.

Partial thromboplastin time (PTT) is used to assess this pathway

Stage Ia (extrinsic pathway)

trauma to vascular wall or extravascular tissue

↓

release of TF

↓

activation of Factor VII

↓

activation of Factor X

↓

cleaving of prothrombin to thrombin (accelerated by Factor V)

↓

formation of prothombin activator via Factor X, Factor V, and Ca+

[image] 

PT (reported in INR)

extrinsic pathway

Stage Ib (intrinsic pathway)

blood trauma or exposure of blood to vascular wall collagen

↓

activation of Factor XII, release of vWF, TXA2, ADP

↓

activation of Factors XI, IX, VII + Ca+

↓

activation of Factor X and V

↓

cleaving of prothrombin to thrombin (accelerated by Factor V)

↓

formation of prothombin activator 

[image] 

how is unfractionated heparin tx monitored?

PTT (aPTT/PTT)

intrinsic pathway

what coag factor is formed in stage II and acts on Fibrinogen to form fibrin monomer?

what factor stabilizes fibrin monomer to form stable fibrin bands?

Thrombin is formed in stage II and acts on Fibrinogen to form fibrin monomer

Factor XIII (released from platelets) stabilizes fibrin monomer to form stable fibrin bands?

DIC

Dissiminated Intravascular Coagulation

Consumptive coagulopathy is a syndrome cx by bleeding due to a depletion of the clotting factors secondary to excessive intravascular thrombosis

plasmin

plasmin is formed by the activation of plasminogen by plasminogen activator (t-PA)

what substance combines with anti-thrombin III cofactor to suppress fibrin formation?

what cells secrete this substance?

Heparin

Basophils and pericapillary mast cells

fibrin is directly inactivated by ____________

fibrin formation is suppressed by ____________

fibrin is directly inactivated by AT3 (antithrombin III)

fibrin formation is suppressed by Heparin (+ AT3)

what is more common:  acquired or genetic hypercoaguable states?

give exampes of acquired and genetic causes of hypercoag states

aquired > genetic

aquired:

increased platelet function (smoking, ↑ chol, atherosclerosis)

accelerated activation of coag system (↑ estrogen, CA, post-surgery)

genetic:

antiphospholipid syndrome

deficiency of natural anticoags

vitamin C deficiency (Scurvy), hemorrhagic telangiectasia (Weber-Osler-Rendu) and Cushings Disease lead to bleeding disorders by what mechanism?

what would you see on PE?

vitamin C deficiency (Scurvy)

hemorrhagic telangiectasia (Weber-Osler-Rendu)

Cushings Disease

↓

damaged or weak vessels ( ↓ vascular integrity)

PE:  purpura, petechiae

what disease causes bleeding disordered due to platelet abnormalities?

sulfa, penicillin, and cephalosporin ABX and quinine cause bleeding disorders by what mechanism?

how is this different than bleeding disorders due to radiation exposure?

sulfa, penicillin, and cephalosporin ABX and quinine cause bleeding disorders due to ↓ platelet counts

radiation exposure causes bleeding disorders due to ↑ platelet counts

von Willebrand's disease = defect in platelet adherence

ASA = defect in platelet aggregation (irreversible)

NSAIDs = defect in platelet aggrecation (reversible)

Uremia = ↑ platelet inhibitory factors, ↓ TXA2

(Uremia infor from  http://emedicine.medscape.com/article/201722-overview)

which anticoagulant drug affects Vitamin K (Factors II, VII, IX, X)?

monitored by which test?

Antidote?

Warfarin (Coumadin)

PT test

Antidote:  Vitamin K, fresh frozen plasma

which anticoagulant drug inhibits the action of thrombin?

monitored by which test?

Antidote?

Heparin

PTT test

intrinsic pathway

Antidote:  protamine sulfate

what congenital (2) and aquired disorders (2) are associated with deficiencies in coagulation factor synthesis/funtion or increased consuption of coagulation factors?

What type of bleeding is cx of theses disorders?

congenital:

Hemophilia A (Factor VIII deficiency)

Hemophilia B / Christmas Disease (Factor IX deficiency)

aquired:

liver disease

Vitamin K deficiency

Evidence/bleeding: 

deep hemorrhages and hemarthroses

Hemophilia A = Factor VIII deficiency

Hemophilia B / Christmas Disease  = Factor IX deficiency

Thrombolytic drugs

t-PA (tissue plasminogen activator)

Streptokinase

Urokinase

Mechanism of DIC

trauma, CA initiate the _______ pathway

s

tasis of blood, immune and infectious (endotoxins) etiolgy initiate the _______ pathway

↓

unregulated generation of ________ leads to systemic fibrin formation

↓

clot formation consumes coagulation factors and __________

↓

intravascular coagulation and bleeding

Mechanism of DIC

trauma, CA initiate the extrinsic pathway

stasis of blood, immune and infectious (endotoxins) etiolgy initiate the intrinsic pathway

↓

unregulated generation of thrombin leads to systemic fibrin formation

↓

clot formation consumes coagulation factors and platelets

↓

intravascular coagulation and bleeding

Hematology

one of the mechanisms of erythropoiesis is the release of erythropoietin from the kidney in response to tissue hypoxia

stimulation of hematopoietic stem cells comes from what growth factors?

originate in blood cells (2)

originated from tissues/organs (3)

Originate from blood cells:

Cytokines:  Colony Stimulating Factors (CSFs)

Interleukins

Originate from Tissues/Organs:

Erythropoietin

Thrombopoietin

Leukopoietin

Adult: 

axial skeleton

proximal epiphyses (long bones)

skull

lymph nodes

Fetus: 

yolk sac

placenta → shifts by the end of gestation to...

bone marrow, spleen, liver, lymph nodes

HgbF (HbF)

HbF should be replaced by HbA after ~3months to adapt to the changing oxygen supply system/demands (placenta vs. lungs)

NOTE:  HbF and HbA2 are increased in beta-thalassemia

MCHC

decreased in IDA

secondary (acquired) hemochromatosis can be caused by thalassemia, sideroblastic anemia, hemolytic anemia, or chronic EtOH**

**EToH was Pepe's only reason for seconday hemochomatosis but actually is less common than other causes

Hemochormatosis = too much Fe build up in the body, especially the liver.

secondary polycythemia**

**can also be caused by a EPO secreting tumor

primary polycythemias are due to genetic mutations causing abnormally high RBC precursors

e.g. polycythemia vera

what are the three morphologic classifications of anemias?

give the name/mechanism for anemias for each category

Microcytic, hypochromic

IDA

Thallassemia

Sideroblastic anemia

Normocytic, normochromic

Hemolytic anemias

acute blood loss

anemia of chronic disease

aplastic anemia

sickle cell anemia

Macrocytic, normochromic

Megaloblastic anemias:  B12 deficiency, pernicious anemia, folate deficiency

Macrophages and lymphocytes sequester iron in the spleen

lymphocytes release cytokines that suppress EPO action/production

abnormal nucleic acid synthesis causes abnormal RBC membrane synthesis and maturation.

pathophysiology of what type of anemia?

megaloblastic anemia:

vitamin B12 and folate deficiencies

what is an inherited hematologic disorder cx by oxidation of RBCs to form Heinz bodies?

what morphological type of anemia is this?

G6PD deficiency

normocitic, normochromic anemia

due to inc. loss or destruction of RBCs

sickle cell disease is a homozygous (rr) genetic trait

sickle cell trait is heterozygous (Rr) genetic trait and will not cause sickle cell anemia (but does provide immunity to malaria)

monocyte

in tissues = macrophage, myeloid dendritic cell

CML

chronic myelogenous leukemia

Inflammation

vascular response to acute inflammation:

constriction of small vessels

dilation of arterioles/venues

keeps infection localzed

what type of WBC invovled in the inflammatory response is capable of dividing and surviving at the site of inflammation? 

what immune response do these cells help activate/coordinate?

what substance do they produce to suppress further inflammation and intiate healing?

Macrophages

involved in activating the adaptive immune response

secrete cytokines to suppress further inflammation and intiate healing

complement system

clotting system

kinin system

Histamine

Serotonin

IL-6, 1beta

TNF-alpha

TFG-beta

INF-gamma

IL6-TNFalpha-TFGbeta-INFgamma

what cytokine is secreted mostly my macrophages and helps initiate the inflammatory response and increases pro-inflammatory proteins in the liver?

what can this cytokine cause in prolonged infection?

TNF-alpha

can cause muscle wasting and cachexia in prolonged infection

__________ is a systemic sign of inflammation that is initiated by exogenous and endogenous pyrogenes.

Fever is a systemic sign of inflammation that is initiated by exogenous and endogenous pyrogenes.

histoplasmosis***

TB

parasites

syphilis

____________ cells do not undergo mitosis (cannot divide or regenerate).  Ex.  nerve cells, cardiac muscle, skeletal muscle cells

what is formed once these cells are destroyed?

Permanent/fixed cells do not undergo mitosis (cannot divide or regenerate).  Ex.  nerve cells, cardiac muscle, skeletal muscle cells

scar tissue (collagen) replaces destroyed/damaged cells

how long after an injury does the maturation phase begin? 

what happens to scar tissue in this phase?

maturation begins 3 weeks after injury (can last >6months)

scar tissue is remodeled and becomes avascular

secondary intention

in primary intention, there is minimal tissue loss and so the wound heals by opposition of wound edges (Ex. surgical incision)

what leads to dysfunctional wound healing by inhibiting fibroblast migration to the wound and impairing angiogenesis, wound contraction, and epithelialization

classical pathway (antigen-antibody)

lectin pathway (bacterial CHOs)

alternative pathway (gram negative bacteria, fungal cell wall components)

Opsonization

Mast cell degranulation

Leukocyte chemotaxis

Cell lysis