Bleeding, Thrombotic and Fibrinolytic Disorders Flashcards
What are the 3 platetelet disorders?
Immune Thrombocytopenia
Thrombotic thrombocytopenia purpura
Hemolytic uremic syndrome
What are the hallmark signs of a platelet disorder?
petechiae and purpura (should maintain the color if pressed on)
What are the causes of ITP?
4
Primary: idiopathic Secondary: Autoimmune Medications Viral infections
What medications can cause ITP?
4
sulfonamides,
thiazides,
cimetidine,
Heparin
What are examples of infections that can cause ITP?
2
HIV, Hepatitis C
What is ITP in children often provoked by?
viral illness
Is ITP better in adults or children?
Better and more transiet in children
Onset 2-21 days after viral infection with spontaneous resolution
Adults are often more chronic
Describe the pathology of ITP?
3
Antibodies bind platelets
Leads to destruction of platelets
Inadequate production of platelets
The disease process of ITP exlplained again?
4
1) Increased platelet destruction is caused by autoantibody binding to platelets.
2) Increased endogenous thrombopoietin (TPO) clearance results in reduced levels.
3) Megakaryocytes may be damaged by antibodies, making them less productive than normal.
4) Suboptimal platelet production results from damaged megakaryocytes and reduced TPO levels.
- antibodiies tag platelets for destruction by the spleen
- Becuase of destruciton of platelts, TPO clearence is increased (more is excreted)
- megakaryocytes are damaged
- overall, low platelet levels, damgaed megakaryocytes and low TPO levels
Clinical manifestations of ITP?
8
- Mucocutaneous bleeding (blood blisters in mouth)
- Petechiae, purpura
- Spontaneous bruising
- Nosebleeds
- gingival bleeding
- Retinal hemorrhage
- Excessive menstrual bleeding
- Melena, hematuria
Labs and procedures for diagnosing ITP and exclusing other things
6
2 positive tests
2 tests that may indicate ITP
2 tests that should be normal if they have ITP
- Thrombocytopenia
- Prolonged bleeding time (after a cut)
- Normal or increased number of megakaryocytes
- +/- anemia
- PT/PTT are normal
- Bone marrow biopsy
- Normal RBC morphology
When should we treat ITP?
2
Don’t treat unless platelet counts are less than 20,000-30,000 or if there is significant bleeding
What should we treat ITP with if we are going to treat it?
3
- Oral steroids with prednisone or dexamethasone
- (if its not working then give IVIG)
- May give platelet transfusion if needed
If a patient fails to respond to oral steriods for ITP treatment what are the other options?
5
- IVIG or anti-D immune globulin
- Rituximab (antibody against CD20)
- Thrombopoietin receptor agonist
- Splenectomy
- For severe cases bone marrow transplant or various chemotherapy agents
What is TTP?
disorder of inappropriate platelet aggregation that leads to destruction of RBCs.
What is the function of ADAMT13?
responsible for cleaving large vWF molecules into smaller peices
Pathgology behind TTP?
3
- Antibodies against ADAMTS-13 which is responsible for cleaving large vWF molecules into smaller pieces
- Extensive platelet aggregation and fibrin bridging
- Shear force on RBCs lead to destruction
TTP is characterized by what three things?
- Thrombocytopenia
- Inappropriate platelet aggregation and formation of fibrin
- Anemia from the RBCs lysing secondary to the shear forces encountered due to the extensive microemboli
Primary causes of TTP?
Autoimmune
Secondary causes of TTP?
5
Cancer Bone marrow transplant Pregnancy Meds HIV
Meds that can cause TTP?
9
acyclovir, Quinine, ticlodipine, clopidogrel, prasugrel, cyclosporine, mitomycin, tacrolimus, interferon alpha
Antiviral drugs (acyclovir)
Quinine
Oxymorphone
Platelet aggregation inhibitors (ticlopidine, clopidogrel, and prasugrel)
Immunosuppressants (cyclosporine, mitomycin, tacrolimus/FK506, interferon-α)
Hormone altering drugs (estrogens, contraceptives, hormone replacement therapy)[12
Where does organ damage primarily occur in TTP?
Why does it cause organ damage?
kidneys and the brain
Microscopic clotting leads to end organ damage due to ischemia
What are the five main characteristic of TTP?
- Thrombocytopenia
- Microangiopathic hemolytic anemia
- Neurologic symptoms
- Kidney failure (may be mild or absent)
- Fever (75% of patients)
Symptoms caused by secondary effecs of underlying microvascular clotting disorder?
4
- Malaise
- Diarrhea
- Thrombocytopenia = bruising, bleeding
- Microvascular clotting leads to organ damage = kidney failure, neurologic symptoms and others
What lab abnormalities would we see in TTP?
5
- Microangiopathic hemolytic anemia (prominent rbc fragmentation)
- Elevated indirect bilirubin
- Decreased serum haptoglobin
- Severely elevated LDH (lactate dehydrogenase)
- Anemia
- High indirect bili
- Low serum haptoglobin
- REALLY high LDH
- presence of shishtocytes
Treatment of TTP?
What is the main treatment and what is essential in treating the disease successfully?
Main treatment is plasma exchange
Early diagnosis and treatment is essential
Without treatment 90% of patients die
What is hemolytic uremic syndrome most commonly causes by?
Can be caused by other things what are they?
10
E. Coli
E. Coli 0157:H7 Shigella dysenteriae Streptococcus pneumonia Quinine Chemotherapy drugs Cyclosporine Anti-platelet medications Pregnancy HIV Genetic
What kind of bacteria causes hemolytic uremic syndrome?
gram negative bacteria because of exotoxin release from these organims
WHat is HUS secondarily caused by?
enodthelial damage
- Widespread injury throughout the body
- sevre inflammation response to hemolyic anemia
Endothelial damage and inappropriate platelet aggregation lead to significant morbodity in HUS. How?
3
Microangiopathic hemolytic anemia
Acute kidney injury and renal failure
Thrombocytopenia
Signs and Symptoms of HUS
8
- Recent or current bloody diarrhea
- Abdominal pain
- Decreased urine output
- Hematuria
- Renal failure
- Hypertension
- Neurologic changes
- Edema
Treatment of HUS?
4
Generally only supportive measurements:
- Transfuse RBCs and platelets if needed
- Dialysis if symptomatic uremia
- Nutritional and electrolyte support
- If thought to be secondary to an autoimmune process may consider plasma exchange
Who is HUS more common is?
children
MAjor things HUS is caused by?
4
E. Coli
Strep Pneumo
Shigella
meds
What are the four major symtpoms associated with HSP (Henoch-Schönelin purpura)?
4
Palpable purpura
Arthritis/arthralgias
Abdominal pain
Renal disease
What is HSP?
IgA vasculitis
In who do most cases of HSP occur in?
3-15 yo
What can HSP be triggered by?
streptococcal upper respiratory infection
What should we not see in patients with HSP that would disclude other diseases
thrombocytopenia or coagulopathy
no anemia or bleeding
How do we treat HSP?
2
Treatment is supportive with NSAIDs or glucocorticoids
Renal failure from IgA deposition may not be evident for 6 months so follow up is necessary
What lab tests would we do for HSP?
4
- biopsy of the skin lesions,
- CBC,
- CMP,
- urinalysis (may show hematuria, +/- rbc casts, +/- proteinuria)
What are the three bleeding disorders we talked about?
Hemophilia
VonWillebrand’s disease
Disseminated intravascular coagulation
What is hemophilia A caused by?
What is hemophilia B caused by?
What is hemophilia C caused by?
WHat is the most common and the rarest?
Factor VIII deficiency
Factor IX deficiency
Factor XI deficiency
A is the most common 80%
C is the rarest
What kind of bleeding is hemophilia caused by?
What are the most common bleeding sites and what is the most dangerous that we are at risk for?
5
Characteristic of this disease is spontaneous hemarthrosis (bleeding into the joint. not trauma induced)
At risk for spontaneous intracerebral hemorrhage
Most common bleeding sites:
Joints: knees, ankles, elbows
Skin, muscle
GU, GI
What is a major complication of hemophilia and what can it lead to?
Hemophillic arthropathy
Development of antibodies to the clotting factor concentrate that we treat with
What is the treatment for hemophilia?
lifelong replacement of deficient clotting factor.
-cyroprecipitate
How often do we replace the clotting factor and how?
usually 3 times per week
IV bolus for home administration
Why would we give an extra dose of clotting factor to hemophilia pts?
Extra dose given if needed due to trauma or suspicion of joint bleeding
What should we avoid with hemophilia pts?
avoid aspirin
What other medications could we give them?
DDVAP
What lab diagnostics would we use to diagnose hemophilia?
2 things that are positive to diagnose
4 that should be normal and rule out other disease
- PTT is prolonged (PTT associated with factor 8)
- Diagnosis is confirmed by decreased levels of Factor VIII, IX or XI
- PT (extrinsic pathway), Bleeding time,
Platelets,
vonWillebrand factor are normal
Do hemophiliacs
a) bleed longer
b) bleed more quickly
c) have a shortened life span
a. yes
b. no
c. only if they dont have access to factor replacement therapy
What are the two main funcitons of von Willebrand factor?
- Binds platelets to form the initial platelet plug
2. Binds with Factor VIII to prolong it’s half life
HOw is VWD inherited?
Which type is the most common?
Autosomal dominant affecting both sexes equally
most common inherited bleeding disorder
Type1
Pathology of Type 1 VWD?
Quantitative abnormality of vWF (molecule is normal but they just dont have enough)
Pathology of type 2 VWD?
What does it clinically resemble?
- Qualitative abnormality
- Decreased binding to factor VIII and platelets (doesnt bind the way it should)
Clinically resembles hemophilia A
Pathology of Type 3 VWD?
Rare
Undetectable levels of vWF and severe bleeding in infancy and childhood
Symtpoms of VWD?
3
- Easy bruising,
- skin bleeding,
- prolonged bleeding from mucosal surfaces
Personal and family history questions for the diagnosis of WVD?
4
- Nosebleeds > 10 min in childhood
- Lifelong easy bruising (associated hematoma)
- Bleeding following dental extractions or other surgery
- Heavy menstrual bleeding or post partum
What lab tests would we do to diagnose VWD?
Three would test positive for VWD
Two tests that should be normal for VWD
Plasma vWF antigen
Plasma vWF activity
–vWF:Rco and vWF collagen
Factor VIII activity
PT normal
PTT normal or prolonged depending on the Factor VIII activity
How would we treat Type 1 VWD for:
Minor Bleeding
Major bleeding
DDAVP
DDAVP, vWF concentrate
HOw would we treat Type 2 VWD for:
Minor bleeding
Major bleeding
DDAVP, vWF concentrate
vWF concentrate
HOw would you treat type 3 VWD for:
Minor bleeding
Major bleeding
vWF concentrate
vWF concentrate
What treatment would we avoid?
aspirin or other NSAIDs
What causes DIC?
WHat does this set off?
4
Massive release of tissue factor (sepsis or trauma)
- Tissue factor then sets the coagulation system in place
- Coagulation occurs
- Clotting factors and inhibitors are consumed
- Clots further trap circulating platelets leading to ischemia (from the clots)
Widespread clotting occurs in DIC as mentioned above. What is occurring simultaneously?
excess thrombin activates plasmin resulting in fibrinolysis.
What does fibrinolysis caused by the excess thrombin (breakdown of clots) result in?
Besides fibrinolysis, what does plasmin also activate?
fibrin degradation products which have further anticoagulant properties
Plasmin also activates the complement and kinin systems = shock
-inflammation (kinin) = dilation = shock
Causes of DIC?
5
Cancer Obstetric complications Sepsis (infection) Massive tissue injury -Trauma -Burns -hyperthermia Snake bite
Clinical manifestations of DIC?
6
Thrombosis and hemorrhage Petechia, purpura, gangrene Renal failure, liver failure
In cancer patients it can be of slow onset
What labs would we do to diagnose DIC?
5
- Thrombocytopenia
- Prolongation of PT and PTT (dont have enough clotting factors left)
- Low fibrinogen (has been converted to fibrin for the clots)
- Increased levels of fibrinogen degradation products (d-Dimer)-lab test
- Schistocytes (helmet cells)- torn in half
What is treatment targeted at in DIC?
targeted at the underlying cause and is otherwise supportive.
When would we use anticoagulants in treatment of DIC?
Why only in this case?
What about if the PT/INR is significantly elevated in DIC?
Anticoagulants only to prevent imminent death
-clot in the lungs for example. only if it outweighs the risk
going to shift. will now be clotting more and higher risk for losing extremities
Fresh frozen plasma or cryoprecipitate to keep fibrinogen > 100 mg/dL
What are the factors that cause hypercoaguable states (clotting disorders)?
What are some examples of things that cause endothelial damage that could cause clotting?4
- Endothelial damage and inflammation
- Elevated platelet levels
Atherosclerosis
Diabetes mellitus
Tobacco use
Cancers
Conditions that accelerate the activity of the clotting system?
9
Pregnancy Oral contraceptives Postsurgical state Malignancy Hereditary clotting disorders Stasis/Immobility Low cardiac output (CHF) Obesity Sleep apnea
What does Protein C do?
What will a deficiency in protein C result in?
inactivates Factors V and VIII thereby inhibiting coagulation
leads to prolonged action of Factors V and VIII leading to excessive clotting
Signs and symptoms of protein C deficiency?
4
Thrombosis
Deep vein thrombosis
Pulmonary embolism
Thrombophlebitis
What labs would we do to daignose protein C deficiency?
5
- Protein C (low)
- PTT, PT (see if extrinsic and intrinsic pathways work-they should)
- Thrombin time (fast)
- Bleeding time (slow)
- Medical and family history may be revealing for a history of thromboembolism
How would we treat Protein C?
2
- Treat with anticoagulants if at high risk for clotting such as surgery or hospitalization
- Chronic anticoagulation if history of thrombosis
Dont treat unless they have clot formation
No prophylactic treatment
What is the funciton of protein S?
What would a deficiency is protein C cause?
Protein S is needed for proper function of Protein C
A deficiency in Protein S results in diminished ability of Protein C to inactivate Factors V and VIII resulting in excessive clotting
Symptoms, diagnosis and treatment for protein S deficiency?
same as protein C
How is antithrombin deficiency inherited?
Usually autosomal dominant
Cinical manifestations?
3
Recurrent venous thrombosis, pulmonary embolism and repetitive intrauterine fetal death
When is the peak age of onset for antithrombin deficiency?
15-35 yo
What is antithrombins function?
regulate clotting
-Major inhibitor of thrombin and other clotting Factors including X and IX
What does antithrombin deficiency lead to?
increased tendency to form clots.
-no inhibtion of clotting factors so they are in the blood stream longer = increasing risk of thrmobus formation
Lab tests for diagnosing antithrombin deficiency?
What will indicate the disease and what will be normal?
- Antithrombin-heparin cofactor assay is the best screening test for AT deficiency
- -Measures functional AT activity
If patients are on anticoagulants or are in the midst of a thrombotic crisis the test results can be skewed (same for Protein C & S)
Standard coagulation tests should be normal (PT, PTT)
How do we treat antithrombin deficiency?
same as protein C and S disorders
Whats the most common genetic disorder to cause DVT?
Factor V Leiden
What does a lack of factor V Leiden result in?
Blood has an increased tendency to clot and is most likely to occur in the veins
Lack of Factor V Leiden decreases the anticoagulant activity of the activated protein C
Factor V Leiden Disease is asymptomatic until a clot forms resulting in the following disorders?
3
Thrombophlebitis
Deep vein thrombosis
Pulmonary embolism
Treatment of Factor V Leiden Disease?
Chronic anticoagulation if presenting with blood clots
If no history of thrombosis then only use anticoagulants if at risk for clots due to hospitalization or surgery
What is Antiphospholipid antibody?
Autoimmune hypercoagulable state caused by antiphospholipid antibodies
Antibodies lead to arterial and venous clot formation
Could cause end organ damage
What are pregnancy complications of Antiphospholipid antibody?
4
miscarriage,
stillbirth,
preterm delivery,
severe eclampsia
Examples of Antiphospholipid antibodies?
3
What can these these antibodies cause? 3
Lupus anticoagulant
Anti-cardiolipin antibody
Anti-beta2-glycoprotein-I
DVT, stroke, miscarriage
Primary or secondary causes of antiphopholipid antibody syndrome?
2
Primary
No other related disease to cause abnormal antibodies
Secondary
Other autoimmune disorders such as Lupus
How do we diagnose antiphopholipid antibody syndrome?
4
Anti-cardiolipin antibodies IgG and IgM OR Lupus anticoagulant OR Anti-beta2 glycoprotein I IgG and/or IgM
Plus history of arterial or venous thrombosis
How do we treat APS?
2
chronic anticoagulation and antiplatelet therapy.
Aspirin
Warfarin or other oral long term anticoagulants
