Pathophysiology of Bleeding Disorders Flashcards
During Vascular Injury, Vasoconstriction platelet plug formation happens in three steps, what are they?
1) platelet adhesion
2) platelet activation
3) platelet aggregation
after Vasoconstriction platelet plug formation happens, what happens next?
clotting cascade
after the clotting cascade, then what happens?
prothrombin activator
so we know prothrombin happens after the clotting cascade, what is the next step?
it converts prothrombin to thrombin
after prothrombin is converted to thrombin, what is the next step?
fibrinogen is converted to fibrin monomer
so fibrin monomer is created how does it become a cross linked fibrin fiber?
it combines with another fibrin monomer and the two are changed into a crossllinked fibrin fiber via factor VIII?
what is factor VIII?
it converts the fibrin factor to cross linked fibrin fiber
what are the factors the initiate clot formation?
Trauma to the vascular wall and adjacent tissues
Trauma to the blood
Contact of the blood with: -damaged endothelial cells collagen -other tissue elements -outside the blood vessel
what does the activation of the clotting cascade cause?
the formation of the prothrombin activator
what does the prothrombin activator cause?
prothrombin conversion to thrombin and all the subsequent
clotting steps
It is a rate limiting step in a process of coagulation
what are the two ways the prothrombin factor is formed?
extrinsic and intrinsic pathway
what is the extrinsic pathway?
hat begins with trauma from the outside to the blood vessel and surrounding tissues
what is the intrinsic pathway?
that begins with trauma from the inside of the blood vessel and the damage to the blood itself
what are the different plasma proteins called that we find in both the extrinsic and intrinsic pathway?
the blood clotting factors
blood clotting factors are inactive forms of ?
proteolytic enzymes
what is the effect when the proteins of the blood clotting factors become active?
their enzymatic actions cause the successive, cascading reactions of the clotting process
what are the intrinsic factors involved in the prevention of blood clotting?
Smoothness of the endothelial cell surface
Layer of glycocalyx on the endothelium
Thrombomodulin
why does the smoothness of the endothelial cell surface prevent blood clotting (intrinsic factor)?
prevents contact activation of the intrinsic clotting system
why does the Layer of glycocalyx on the endothelium prevent blood clotting (intrinsic factor)?
Covers endothelial cells
and Repels clotting factors and platelets
why does thrombomodulin prevent blood clotting (intrinsic factor)?
Protein within endothelial membrane binds and inactivates thrombin to become a Thrombomodulin- Thrombin complex which
Activates plasma protein C
which is an anticoagulant that Inactivates factors Va and VIIIa
what does thrombomodulin activate? why is this significant in terms of blood clotting
Activates plasma protein C
what does protein C require?
requires the presence of co-factor-Protein S
what are some important blood coagulation tests?
bleeding time
whole blood clotting time
thrombin time
what is the bleeding time test?
Piercing of the tip of the finger or lobe of the ear, bleeding ordinarily lasts for 1 to 5 minutes.
The time depends largely on the depth of the wound and the degree of hyperemia in the finger or ear lobe at the time of the test.
Lack of any one of several of the clotting factors can prolong the bleeding time, but it is especially prolonged by lack of platelets (thrombocytopenia)
note* if just missing the factor V, the rest of the factors are okay however if there is a problem at the combination step then problems can arise
so if there are problems in platelet plug formation what does that do to the bleeding time?
it increases it
what is the whole blood clotting time test?
Measuring the amount of time needed for blood to clot in the tube (6-10 minutes)
Not reliable
what is the thrombin time test?
Estimates the fibrinogen concentration in the blood and so it becomes the time taken by plasma to clot after adding standardized thrombin to it
normal count: 15 sec
what DOES the thrombin time test?
it tests the common clotting pathway
what is the partial thromboplastin time (PTT) test?
it measures the activity of the intrinsic pathway and used for the therapeutic monitoring of Heparin
what are the factors required for PTT?
fibrinogen (I), prothrombin (II), V, VIII, IX, X, XI, & XII
what is heparin?
inhibits the activity of factors XII, XI, X, and IX= Intrinsic pathway
what is the normal value of the partial thromboplastin time (PTT)?
normal value is 25-40 sec
what is the prothrombin time (PT)test?
Used for therapeutic monitoring of Warfarin, measures the common pathway, and It measures the activity of the EXTRINSIC pathway (In conjunction with PTT)
what are the factors required for the prothrombin time test (PT)?
It requires the activity of factors I,II,V,VII,X; factor VII INITIATES it
what is the normal value of the prothrombin time test (PT)?
11-15 sec
what is warfarin?
lowers down Vitamin K levels which carboxylates factor VII (short half life)
what is the effect of prolongation of PT? treatment? What about if urgency needed?
Warfarin overdose; administer vitamin K; administer fresh frozen plasma (contains factor VII)
how do we differentiate a thrombocyte problem or clotting cascade problem?
if there is abnormal bleeding then there are causes that can determine if its one or the other:
quantitative platelet dysfunciton (platelet count <150K)
qualitative platelet dysfunction (increase bleeding time)
coagulation factor deficiency (abnormal coagulation studies)
what drug can we use to treat abnormal bleeding that is due to quantitative platelet dysfunction caused by decreased production?
sulfonylurea; note that since there is decreased production there is increased destruction
what is factor V Leiden?
Abnormal factor V- called Factor V Leiden can not be broken down by protein C, which is usually under the control of protein C, usually affecting caucasian population
what is the result of factor V Leiden?
Excessive Coagulation can lead to Thrombosis which in Pregnancy leads to Eclampsia and usually in patients with thromboembolic complications
how does factor V normally function?
Factor V acts as a cofactor on factor X leading to formation of prothrombin activator which is under the control of protein C which degrades factor V preventing excessive coagulation
what is thrombocytopenia?
presence of relatively few platelets in the blood usually less than 100,000 below the normal range of 150000 and 450000 per mm^3
what are the symptoms of thrombocytopenia?
brusing and petechiae (reddish and purplish spot due to bleeding)
what are the indicators for Thrombocytopenia?
pregnancy and transfusion-increase in blood volume
what are the causes of thrombocytopenia?
increased destruction
- Idiopathic thrombocytopenia (ITA)
- Thrombotic thrombocytopenia (TTP)
- Disseminated intravascular coagulation (DIC)
- Drug (heparin, antibiotics)
decreased production
- Marrow infiltration with tumor, lymphoma
- Infection (HIV, mumps)
- Nutritional deficiency (folate, B12)
- Drugs (chemotherapy, alcohol)
- Genetic (hereditary disorders)
what is thrombocytosis/thrombocythemia?
Presence of high platelet counts in the blood and can be either: reactive or primary (also termed essential and caused by a myeloproliferative disease).
It can predispose to thrombosis in some patients
what is a cause of pulmonary embolism? how is it treated?
Deep vein thrombosis; clot dissolving drugs such as TPA
what is aplastic anemia?
Inadequate number/abnormal activity of multipotent myeloid stem cells (no blood cell production)
what is the cause of aplastic anemia?
Viruses (HIV), Chemicals, Radiation, Renal failure (decrease erythropoietin) or it can be IDIOPATHIC
what are drugs that can cause aplastic anemia?
NSAIDs, Chloramphenicol, and CHEMICALS: Benzene
what are the symptoms of aplastic anemia?
Pancytopenia (small spots and all over), Thrombocytopenia: Mucosal bleeding, Petechia
Anemia: Fatigue, Pallor
Neutropenia: Frequent infections
what is Fanconi Anemia (not syndrome=kidney disease)?
Autosomal recessive genetic condition
Genetic defect affects a cluster of proteins responsible for DNA repair (BRCA-2 gene) leading to progressive and complete bone marrow failure by the age of 40. Patients develop AM leukemia/Myelodysplastic syndrome with Neutropenia also associated with this condition (recurrent infections)
what are the symptoms of Fanconi Anemia?
Multiple birth defect (lack of thumbs, kidney defect, eyes defects)
what is the therapy for Fanconi Anemia?
Androgens, Hematopoietic growth factors- ULTIMATE: Bone Marrow Transplant
what is Disseminated Intravascular Coagulation (DIC)?
Defined as acquired clinical symptom characterized by a wide spread activation of coagulation
what is Disseminated Intravascular Coagulation (DIC) classified as?
consumptive thromboembolic disorder
what is the result of Disseminated Intravascular Coagulation (DIC)?
Widespread formation of fibrin clots in medium and small vessels
what are the causes of Disseminated Intravascular Coagulation (DIC)?
- cancers, acute myeloid leukemia (particularly APML)
- Abruptio placentae, pre-eclampsia, amniotic fluid embolism
- Trauma
- Infections: anything gram negative sepsis
- Heat Stroke
- Viral: Arenaviruses causing Argentine hemorrhagic fever or Bolivian Hemorrhagic Fever
what is the mechanism of DIC? name the two?
Release of tissue factor or thromboplastic substances into the circulation
Widespread injury to the endothelial cells
describe the first major mechanism of DIC:
Release of tissue factor or thromboplastic substances into the circulation
Tissue factor is released from the damaged tissues
Thromboplastic substances are released from variety of sources like the placenta, cytoplasmic granules, and mucus
describe the second major mechanism of DIC:
Injuries that cause endothelial cell necrosis expose subendothelial matrix causing activation of platelets and coagulation pathway+ release of TNF
Deposition of antigen-antibody complexes like
Systemic lupus erythematosus, Temperature extremes, Microorganisms (meningococci, rickettsiae), prone to DIC
Result: Activation of complement= endothelium damage
what is the role of tumor necrosis factor in DIC?
TNF induces endothelial cells to express tissue factor on their surface and to decrease the expression of thrombomodulin
TNF up-regulates the expression of adhesion molecules on endothelial cells
*widely implicated in the pathogenesis of DIC
what are the causes to DIC?
massive tissue destruction, sepsis, endothelial injury which release widespread microvascular thrombosis
so in a patient with DIC, what happens after the widespread microvascular thrombosis? what does this ultimately lead too?
fibrinolysis, ischemic tissue damage, consumption of clotting factors and platelets all resulting in bleeding
for hemophilia type A, what is missing?
Deficiency of Factor VIII
MOST COMMON type of hemophilia
Variable penetrance
for hemophilia type B, what is missing?
Deficiency of Factor IX ROYAL DISEASE
how are vascular/platelet disorders characterized?
bleeding is usually confined to the skin
it usually takes the form of confluent petechiae and small ecchymosis
spontaneous bleeding is common
wound bleeding is excessive
how are coagulation disorders characterized?
bleeding is in deeper tissues
bleeding usually takes the form of large ecchymoses
spontaneous bleeding is uncommon
wound bleeding is less profuse
