ASF - Bleeding Disorders (Squires) Flashcards
What specific toxin can lead to aplastic anemia?
Benzene
What is the function of glucuronlytransferase on bilirubin?
This enzyme conjugates bilirubin with glucuronic acid, which makes it more soluble and better able to be excreted in the urine
When evaluating a patient for a bleeding disorder, why is it important to ask about current medications the patient might be taking?
Some medications can deplete clotting factors or interfere with the numbers of specific cell types in the blood.
Examples:
Anticoagulants (warfarin, heparin, etc.), aspirin, antibiotics, tricyclic antidepressants, and supplements (vitamins C and E, ginger, garlic)
True or False: The clinical appearance of bleeding can indicate the type of disorder that is most likely.
True
Platelet abnormalities: petechiae, gingival bleeding, epistaxis, immediate post-op bleed
Abnormal coagulation factors: hematomas, hemarthrosis, delayed post-op bleed
What is the clinical term for this condition and which type of bleeding disorder does this kid likely have?
Hemarthrosis
The child most likely has a coagulation factor abnormality. Further testing should be done to determine the specific disorder.
True or False: Coagulation factor abnormalities are more common in males than in females.
True
Coagulation factor abnormalities are more common in males. This is due to the fact that many factor abnormalities are inherited through X-linked recessive genes. Mothers are carriers, and if they pass the diseased allele to a male child, he has a 100% chance of getting the disorder.
What is the name of this condition and which type of bleeding disorder would most likely cause this?
Gingival bleeding
This type of bleeding is most often seen in platelet abnormalities. Other common findings in platelet abnormalities are bruising and petechiae.
Remember that females are more likely to have platelet abnormalities than males.
Which clotting factor abnormality can only be determined by a prothrombin time (PT)?
Factor VII deficiency
Remember:
PT tests factors VII, X, V, II, and I
aPTT tests factors II, V, VIII, IX, X, XI, XII, prekallikrein, high molecular weight kininogen (HMWK) and fibrinogen (factor I)
The only one that does not overlap with aPTT is factor VII, making PT the best option for this test.
Which clotting factors does an activated partial thromboplastin time (aPTT) test for?
Factors II, V, VIII, IX, X, XI, XII, prekallikrein, high molecular weight kininogen (HMWK), and fibrinogen (factor I)
Remember that aPTT tests for the common pathway AND the intrinsic pathway.
Which clotting factors does a prothrombin time (PT) test for?
Factors II, V, X, VII, and I (fibrinogen)
Remember that PT tests the common AND extrinsic pathways
What is a mixing study and what 2 types of factor abnormalities does it detect?
A mixing study is a 1:1 dilution of patient’s plasma with normal plasma that is then analyzed via PT and aPTT.
Mixing studies test whether or not there is a factor deficiency OR a factor inhibitor
If the mixing study leads to a correction in PT/aPTT, then the patient has a factor deficiency.
If the PT/aPTT does not get corrected via mixing study, the patient has a factor inhibitor.
Ideally, when should mixing studies be done to ensure that all factor inhibitors are detected? Why is time an issue?
Mixing studies should be done immediately after the first blood draw and then once more after the sample has been incubated for 30-60 minutes.
Some inhibitors (ex: lupus anticoagulants, factor VIII) are time-dependent and will degrade over time. Adhering to a time schedule ensures that these inhibitors will be detected.
What is the normal range for prothrombin time (PT)?
12.2 - 14.2 seconds
Which test (PT or aPTT) is used to monitor warfain therapy?
PT
Warfarin is an inhibitor of vitamin K, which is required to synthesize factors II, VII, IX, and X. Three out of four of these factors are tested via PT, making it the ideal test for this type of therapy
aPTT is used as a screening tool to detect a specific disease and to manage therapy with a certain drug. Name the disease and drug.
von Willebrand disease and heparin therapy
von Willebrand disease is a platelet deficiency/malfunction that decreases factor VIII half-life in the blood and increases bleeding.
Heparin activates antithrombin III, which inactivates factors in the intrinsic pathway and kallikrein. Because aPTT measures the intrinsic pathway, it is used for this form of thearpy.
What is considered to be a normal range for activated partial thromboplastin time (aPTT)?
23 - 36 seconds
A 33-year-old woman comes into the office complaining of increased bruising, gingival bleeding, and heavy menstrual flow. The results of her labs are as follows: PT = 13.1 sec, aPTT = 43 sec.
Upon performing a mixing study, you retest the PT and aPTT and get 13 sec and 43 sec, respectively. What factor abnormality (deficiency or inhibitor) does your patient have?
Factor inhibitor
Remember that when a mixing study does not correct PT or aPTT, the patient has a factor inhibitor. This is usually due to the fact that patients have an excess of inhibitor, which ends up inactivating the factors in the normal serum sample, preventing the PT/aPTT from changing.
What is a thrombin time (TT) and what is it used for?
Thrombin time (TT) is the time it takes for a fibrin clot to form after the addition of thrombin concentration to patient’s citrated plasma.
TT is used to screen for bleeding disorders (afibrinogenemia, DIC) and effects of anticoagulant drugs (argatroban, lepirudin, tPA, heparin)
What are the levels of fibrinogen in a normal patient and how low can fibrinogen levels go before coagulation is decreased?
170-500 mg/dL
Usually patients with 100 mg/dL or above do not experience any coagulation problems.
What is bleeding time (BT) and why is it no longer used to determine bleeding disorders?
Bleeding time is a test in which the physician makes a small incision on the patient’s arm and measures the time it takes for the bleeding to stop. Normal BT is usually 9-11 minutes.
This is no longer used because it is very subjective and there are better and faster tests available to diagnose bleeding disorders.
What is Light Transmission Aggregometry (LTA) and what does it measure?
LTA - patient’s plasma is mixed with aggregation agonists (ADP, EPI, collagen, ristocetin) and put in a spectrophotometer. The amount of light that shines through is measured. The idea is that platelets that aggregate will create a more cloudy appearance to the plasma, which will decrease light transmission.
LTA measures the ability of platelets to induce platelet aggregation.
Patients with platelet abnormalities will have less aggregation, which will make the plasma less cloudy, allowing more light to shine through the sample.
What are the 4 main platelet aggregation agonists used in light transmission aggregometry (LTA)?
ADP, epinephrine, collagen, and ristocetin
Glanzmann’s Thrombasthenia is characterized by lack of platelet aggregation with all main LTA agonists except what?
Ristocetin
Glanzmann’s is characterized by a lack of aggregation with ADP, collagen, and epinephrine AND increased aggregation with ristocetin.
A 25-year-old male comes to your office complaining of chronic nose bleeds that just won’t stop once they start. He is really stressed out because every time he goes on a date, his nose starts bleeding and scares everyone away. Lab results are below:
Normal PT and aPTT, low platelet count, increased bleeding time.
LTA results: aggregation with ADP, collagen, and epinephrine; no aggregation with ristocetin.
What disease do these lab results indicate?
Bernard-Soulier Syndrome
Remember that Bernard-Soulier syndrome is a platelet deficiency that prevents aggregation with ristocetin, but allows aggregation with ADP, EPI, and collagen.
What is a D-dimer?
A D-dimer is a fibrin degradation product (FDP) that consists of 2 fibrin D molecules connected via an activated factor XIIIa.
What does a high D-dimer indicate?
Disseminated intravascular coagulation (DIC)
Marked increase in D-dimer levels is used as one of the criteria for diagnosing DIC.
A 42-year-old woman complains of what she thinks is a rash on her legs that she has had since childhood. These small lesions have grown progressively worse as she has aged and have started to appear on her lips and hands. She also tells you that she has really bad nose bleeds and that she tends to have bloody diarrhea at times.
Based on these symptoms, what disease does this patient have?
Hereditary Hemorrhagic Telangiectasia (HHT)
HHT presents during childhood with small petechiae that appear to be a rash. Telangiectasia, small petechial spots of the skin, occurs because the microvasculature dilates and swells.
What are the 2 main jobs of von Willebrand Factor (vWF)?
- Facilitates binding of platelets to subendothelim during vascular injury
- Carries factor VIII, prolonging its half-life
Of the three types of von Willebrand Disease, which type best responds to desmopressin (DDAVP) therapy?
Type I
Type I vWD is characterized by a partial deficiency of vWF. Because vWF also prolongs the half-life of factor VIII, this will also be low, leading to mild to moderate bleeding.
Desmopressin facilitates the production of vWF and factor VIII to increase levels back to normal.
This does not work with type II because vWF does not function properly, and does not work with type III because no vWF can be formed.
Which type of von Willebrand disease is considered to have an autosomal recessive inheritance?
Type III
Type III is the most rare and the most severe form of vWD, and is inherited via autosomal recessive.
Types I and II are both autosomal dominant
True or False: Type III von Willebrand Disease is characterized by a complete lack of vWF production.
True
Type I = decreased vWF
Type II = normal vWF levels, but doesn’t function
Type III = no vWF at all
How is type III von Willebrand Disease treated?
Cryoprecipitate and factor VIII
Remember that the typical treatment, desmopressin, is not useful here because the patient cannot make their own vWF.
True or False: Glanzmann’s thrombasthenia and Bernard-Soulier syndrome are both caused by a defective receptor on platelets.
True.
Glanzmann - deficient fibrinogen (GPIIb/IIIa) receptor
Bernard-Soulier - deficient vWF (GPIb/IX/X) receptor
Which syndrome is caused by a lack of alpha-granules in platelets?
Gray Platelet Syndrome
Autosomal recessive disorder characterized by lack of platelet alpha granules.
Defining characteristics: large gray platelets on peripheral smear and reduced platelet aggregation to collagen on LTA.
What does activated factor XIII do and what activates it?
Factor XIIIa is used to cross-link fibrin to increase stability of fibrin clot
Activated by thrombin
What disease should you assume in a patient with a clear bleeding disorder who has a normal platelet count, PT, PTT, and platelet function test?
Factor XIII deficiency
If all else fails, it is factor XIII. All tests will appear normal, but the patient will clearly have bleeding problems.
What are the 4 main causes of thrombocytopenia?
- Decreased production
- Increased destruction
- Sequestration
- Hemodilution
What is sequestration and how does it cause thrombocytopenia?
Sequestration occurs when the spleen retains an increased number of platelets, leading to splenomegaly and thrombocytopenia.
Normal spleen contains 30% of all platelets
Bone marrow destruction is the most common cause of thrombocytopenia that is attributed to decreased production. What are the 3 main main factors that can cause marrow destruction?
- Drugs
- Ex: quinidine, quinine, thiazide, furosemide, indomethacin
- Infections
- Ex: measles/mumps, neonatal infections, CMV
- Alcohol
In what 2 ways can chronic alcohol abuse lead to decreased production of platelets?
Alcohol is toxic to bone marrow, and this can lead to decreased production.
Chronic alcoholics also tend to have low B12 levels, which is also a main cause of decreased platelets.
How does heparin lead to increased destruction of platelets?
Formation of an antibody against heparin-PF-4 complex
Heparin binds platelet factor-4 (PF-4) and forms a neopeptide, which is recognized as foreign by the immune system. IgG against neopeptide formed and binds to neopeptide on platelet –> removal of platelets via spleen AND activation of platelets to induce thrombosis
What are alloantibodies and what two processes typically form them?
Alloantibodies are foreign (aka not previously present) antibodies directed against specific antigens
The two most common causes of alloantibody production are: pregnancy and transfusions
Disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are all types of what type of increased destruction?
Non-immune
What term is used to describe how massive red blood cell transfusions can alter the platelets and coagulation factors?
Hemodilution
A 5-year-old boy is brought into the hospital by his mother. She tells you that her son has been having severe nose bleeds that started after he got over a viral infection a few weeks ago.
What disease is the boy suffering from and what are his treatment options?
Acute Immune Thrombocytopenic Purpura (ITP)
Acute ITP typically occurs in children after exposure to a virus. Symptoms typically last for 2-6 weeks, but spontaneously disappear on their own.
No treatment required
What is the pathophysiology behind Immune Thrombocytopenic Purpura (ITP)?
Formation of autoantibodies against platelet glycoproteins (GPIIb/IIIa, etc.) that increase platelet destruction and decrease platelet production
What are these red lesions called?
Purpura
Splenectomy is one of the preferred treatment methods to fix immune thrombocytopenic purpura. What is the downfall of having patients go through a splenectomy?
Life-long risk of infections increases
Can treat with corticosteroids (preferred treatment) or IVIg before splenectomy.
What is the function of ADAMTS13 and which disease process is caused by a deficiency in this enzyme?
ADAMTS13 is responsible for cleaving aggregates of vWF
vWF aggregations can lead to formation of thrombi in the walls of the vasculature and in the blood.
Thrombotic thrombocytopenic purpura (TTP)
What platelet disorder is caused by E. coli O157 toxin?
Hemolytic uremic syndrome (HUS)
Below is a picture of a glomerulus. What is the name of the structure that the black arrow is point to and what disease is it typically seen in?
Hyaline thrombus
Typically seen in thrombotic thrombocytopenic purpura (TTP)
What is the course of treatment for patients with TTP?
Apheresis (plasma exchange) with fresh frozen plasma
Apheresis separtes blood into components, removes patients plasma, and adds normal plasma to patient’s RBCs before re-infusing the patient.
This will remove the autoantibodies and will add in new ADAMTS13
Which 4 factors are associated with prolonged PT and normal aPTT?
- Factor VII deficiency
- Warfarin therapy
- Mild liver disease
- Moderate vitamin K
Remember that PT is associated with the extrinsic and common pathways, but the main difference between it and aPTT is that it measures factor VII.
Warfarin therapy –> decreased vitamin K –> decreased factor VII
What are the 3 deficiencies that will cause a prolonged aPTT, but do not increase bleeding?
- Prekallikrein deficiency
- High molecular weight kininogen (HMWK) deficiency
- Factor XII deficiency
If a patient’s clotting abnormality (abnormal aPTT) is not corrected with a mixing study, which of the following is the most likely problem?
A. Liver damage
B. Immune-mediated attack of clotting factors
C. Thrombin inhibitor
D. Factor VII deficiency
B. Immune-mediated attack of clotting factors
aPTT that is not corrected via mixing study indicates lupus anticoagulant antibodies, autoantibodies to VIII, or alloantibodies to VIII or IX
Liver damage, depending on severity, could indicate abnormal PT/normal aPTT OR abnormal PT/aPTT
Thrombin inhibitor would be present in a non-corrected mixing study with abnormal PT and PTT
Factor VII deficiency is indicated by abnormal PT
What are 4 possible causes of patients with a prolonged PT and aPTT that does not correct after mixing study?
- Factor II inhibitor
- Factor V inhibitor
- Factor X inhibitor
- Thrombin inhibitor
A 17-year-old male comes into the emergency department with a severely swollen knee and numerous deep red bruises on his legs and torso. He tells you that he hurt his knee and had a bad fall during a soccer game, but the bruising happens all the time. You suspect a clotting factor abnormality and order labs, which indicate a normal PT and a prolonged aPTT.
What condition does the patient likely have? What causes this condition?
Hemophilia
Hemophilia is an X-linked recessive clotting disorder caused by a deficiency in factor VIII (type A) or factor IX (type B).
Key findings that indicate hemophilia: normal PT/prolonged PTT, hemarthrosis, deep hematomas, and male.
What drug is given to hemophiliac patients before they undergo surgery to lessen risk of excessive bleeding?
Desmopressin (DDAVP)
Desmopressin increases production of factor VIII and vWF, which increases the half-life of factor VIII
What is a disease caused by an X-linked recessive deficiency in factor IX?
Hemophilia B
What is the typical treatment for hemophilia C, an autosomal recessive factor XI deficiency?
Treat with fresh frozen plasma
Most common factor deficiencies have a factor concentrate, which is plasma with excess of that specific factor. Because factor XI deficiency is so rare, there is no prepared concentrate, so FFP is used.
Describe the pathophysiology behind the formation of thrombi typical of DIC.
- Sepsis, tissue injury, or endothelial injury leads to release of tissue factor (TF)
- TF binds factor VII and activates coagulation cascade –> fibrin strands and thrombi in microvasculature
- RBCs get shredded by fibrin to form schistocytes that also form thrombi and block microvasculature
What lab findings indicate a patient is in DIC?
- Prolonged PT and aPTT
- Decreased platelet count
- Decreased fibrinogen
- Schistocytes on peripheral smear
- Increased D-dimers
Which two substances become overwhelmed in DIC, which leads to to uninhibited clotting factors?
Antithrombin and Protein C
How does plasmin contribute to the hemorrhagic portion of DIC?
Plasmin cleaves fibrin and makes fibrin degradation products (FDP). These FDPs compete with thrombin, an enzyme that converts fibrinogen into fibrin, leading to decreased clotting abilities. This causes hemorrhage.
What does protein C do?
Inhibits activated factors Va and VIIIa
Slow inhibition of these factors leads to the formation of thrombi in DIC
What does Antithrombin do?
Acts as an inhibitor of thrombin and factors Xa, IXa, and XIa
Involved in DIC
