Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
46 Cards in this Set
- Front
- Back
|
Presentation- Bleeding into joints (hemarthroses) or large muscles. Normal Protime(PT), while the activated partial thromboplastin time (aPTT) is prolonged. The aPTT corrects with the addition of normal plasma(mixing study), indicating a factor deficiency as opposed to an inhibitor. Individual clotting factor levels are then assayed.
|
Hemophilia
Pathology - X-linked recessive trait. ~1/3 are spontaneous mutations -Mutations in the Factor VIII gene cause Hemophilia A (85% of hemophilias) – 1/5000-1/10,000 male births - Mutations in the Factor IX (aka Christmas Factor) gene = Hemophilia B (12% of hemophilias) – 1/30,000 male births - The mutations lead to reduced production of the factor Severe Deficiency < 1% of normal factor levels Moderate Deficiency 1-5% of normal factor levels Mild Deficiency 5-15% of normal factor levels Why do hemophiliacs bleed into the large muscles and joints? The true physiologic activator of clotting is Factor VII with Tissue Factor (TF). FVII and TF start the process, but they're turned off very quickly, and there's a shift toward FVIII and FIX to take over the job of clotting. So, in areas of the body with TF is decreased, FVIII and FIX have to work extra hard. Where is TF lacking, in the joints and large muscles. This explains the bleeding into these areas with a deficiency or absence of FVIII and FIX. |
|
|
Presentation- Bleeding from mucosal surfaces, menorrhagia, bleeding after minor procedures (commonly dental procedures). Usually, has a prolonged aPTT, which would correct with a mixing study. Normal PT.
|
Von Willibrand’s Disease – Most common inherited bleeding condition
Pathology- Mutations in the Von Willibrand’s gene cause either quantitative or qualitative defects of VWF. These defects lead to decreased platelet adhesion and/or decreased Factor VIII levels (VWF carries FVIII in blood). Three types VWD i. Type 1 – Mild to moderate deficiency (autosomal dominant inheritance) ii. Type 2 – Functional Defect (4 subtypes – most of which are autosomal dominant) iii. Type 3 – Absolute deficiency (autosomal recessive trait) Menorrhagia is an abnormally heavy and prolonged menstrual period at regular intervals. |
|
|
Presentation – Easy bruising, hematuria, nosebleeds. Prolongs both PT and PTT. Will correct with a mixing study.
|
Vitamin K deficiency
Pathology – Reduction in the levels of the Vitamin K dependent factors (II, VII, IX, X). Results from a lack of intake of foods rich with Vitamin K (green leafy vegetables), a fat soluble vitamin, or from antibiotics, which will eliminate the gut flora, which is a source of Vitamin K. A functional vitamin K deficiency results from the use of warfarin or the intake of an ingredient in rat poison, brodifacoum. |
|
|
Presentation- Increased bruising, hematuria, joint bleeds, muscle bleeds. The PT or PTT(or both) will be prolonged based on which factor is being inhibited (for example, an inhibitor against FVIII will only cause the PTT to be prolonged, the PT will be normal). The prolonged clotting time will not correct with the addition of normal plasma (mixing study).
|
Factor Inhibitors
The clotting time doesn't improve because the factor inhibitor will bind and inactivate the factor in the normal plasma as well. Pathology – Autoantibody (typically IgG) against a specific factor, which inhibits that factors function. The most common factor affected is Factor VIII. |
|
|
Inherited Platelet problems
|
Inherited Platelet problems
1. Glanzmann’s Thrombasthenia 2. Bernard-Soulier |
|
|
Presentation- Petechiae, nose bleeds, conjunctival hemorrhage. Normal PT and PTT. Normal platelet count.
|
Inherited Platelet problems
Glanzmann’s Thrombasthenia Pathology- Congenital lack of Glycoprotein IIb/IIIa on platelet membrane leads to lack of platelet aggregation. Fibrinogen connects the Glycoprotein IIb/IIIa on platelets to make them aggregate THINK: If the platelet count is normal, and you still aren't getting platelet aggregation, then what's wrong? Platelets aggregates by their Glycoprotein IIb/IIIa receptors, therefore, these symptoms must be caused by a congenital lack of Glycoprotein IIb/IIIa receptors on the platelet. Also THINK: The glass man is also the fiber man. Glanzmann’s Thrombasthenia - fibrinogen - connects GPIIb/GPIIIa on platelets. |
|
|
Presentation- Petechiae, nose bleeds, conjunctival hemorrhage. Normal PT and PTT. Low platelet count.
|
Inherited Platelet problems
Bernard-Soulier - Congenital lack of Glycoprotein Ib on platelet membrane leads to lack of platelet adhesion. THINK: Decreased platelets, means a decreased ability to be able to stick to the endothelial walls. How to platelets stick to the endothelial walls? With GP Ib so low platelets. low GP Ib. Also THINK: Bernard-Soulier - BS Soldiers. What do BS Soldiers do? They don't stick together on the front line. Front line = endothelial wall. No sticking = decreased platelet adhesion. Why? Because of the deficiency in GP Ib. |
|
|
Acquired Platelet Deficiency
|
Acquired Platelet Deficiency
1. Immune Thrombocytopenia Purpura(ITP) 2. Thrombotic Thrombocytopenia Purpura 3. Hemolytic Uremic Syndrome |
|
|
Presentation- Petechiae, nose bleeds, conjunctival hemorrhage. Normal PT and PTT. May have markedly low platelet count (< 5,000/cumm).
|
Acquired Platelet Deficiency
Immune Thrombocytopenia Purpura(ITP) Pathology – Autoantibodies against platelets that leads to rapid consumption of the platelets. When it occurs in children, there is often a viral prodrome, and it is usually self-limiting. In adults, usually no viral prodrome, and can often become a chronic condition. Associated with HIV and pregnancy. ITP is usually seen in younger people. This is advantageous because younger people have less severe bleeding. Why? Because their platelets are large and new, so even though the levels are low, the affect isn't as bad as it would be in an older person with smaller, older platelets. The spleen is NOT enlarge even though it does have to removed the Ab-coated-platelets. THINK: The name gives it away - Immune Thrombocytopenia Purpura. Immune - Abs against platelets Thrombocytopenia - low platelets in the blood (because of the Abs) Purpura: Bleeding causes purple spots when it gets into the tissue. Also THNIK: What cause use the platelets to get sooooo low? Immune attack - Abs |
|
|
Diagnosis - Clinical - Pentad (only found ~50% of time)-
–Microangiopathic hemolytic anemia(MAHA) - CNS symptoms – 60 –70% –Renal dysfunction – 50% –Fever – 25 – 60% –Thrombocytopenia |
Acquired Platelet Deficiency
Thrombotic Thrombocytopenia Purpura Pathology:Etiology related to the lack of ADAMTS-13 – a metalloproteinase that cleaves the ultra large Von Willebrand multimers to large VWF multimers Associated with pregnancy and HIV. |
|
|
Hemolytic Uremic Syndrome
|
Hemolytic Uremic Syndrome
Typically, no deficiency in ADAMTS-13. More often endothelial damage precipitating cause. Infection – most common association, especially E. Coli O157:H7 and Shigella |
|
|
Presentation- These patients present with idiopathic deep venous thromboses or pulmonary emoboli, which are often recurrent. Women may also present with recurrent spontaneous abortions.
|
Venous Thromboembolism(VTE)
Pathology These disorders predispose patients to thrombotic events by loss of inhibition of the coagulation cascade or by enhancing the coagulation system. Diagnosis – Laboratory evaluation can be done for an inherited hyercoagulable condition or APLA/homocysteine in patients with idiopathic VTE •Do NOT check during an acute event as the protein C & S and antithrombin may be physiologically low during that time. Wait until off warfarin to check protein C & S as these are vitamin K dependent If a patient has an unprovoked VTE, then there is a 40% chance of having another VTE in the next 5 years. |
|
|
Inherited Hypercoagulable states
|
Inherited Hypercoagulable states
1. Antithrombin Deficiency 2. Protein C Deficiency 3. Protein S Deficiency 4. Activated Protein C Resistance 5. Prothrombin 20210A Gene Mutation |
|
|
Antithrombin Deficiency
|
Antithrombin Deficiency
•Activity markedly increased by Heparin •Heterozygote prevalence– 0.02-0.04% •25 fold increase in relative risk of VTE |
|
|
Protein C Deficiency
|
Protein C Deficiency
•Needs cofactor Protein S for full activity •Vitamin K dependent enzyme •Heterozygote prevalence - 0.2-0.3% •7-10 fold increase in RR of VTE |
|
|
Protein S Deficiency
|
Protein S Deficiency
•The cofactor for Protein C •Vitamin K dependent •Two forms - bound and free - only free Protein S is active •Heterozygote prevalence - unknown •RR from 7-10 fold increase of VTE |
|
|
Activated Protein C Resistance
|
Activated Protein C Resistance -Most common inherited cause of thrombophilia
• Factor V Leiden Mutation is the most common cause of this condition •The mutation makes FV resistant to inactivation by activated Protein C •Prevalence of heterozygosity –European ethnic populations - 3-7% –Other ethnic groups - << 1% •RR of VTE for –Heterozygotes – Increased 4-fold –Homozygotes - ? Increased 20-80-fold |
|
|
Prothrombin 20210A Gene Mutation
|
Prothrombin 20210A Gene Mutation
•Associated with increased levels of prothrombin in the circulation •Heterozygote prevalence –European ethnic populations - 2% –Other ethnic groups - << 1% •2-3 fold increase in RR of VTE |
|
|
Acquired conditions for Venous Thromboembolism(VTE)
|
Acquired conditions
•Myeloproliferative disorders •Pregnancy •Trauma •Surgery •Immobilization •Age •Nephrotic syndrome •Malignancy •Estrogen •Antiphospholipid Antibodies (APLA) - An autoimmune condition that promotes coagulation – unclear exact mechanism. -Two subtypes – Lupus anticoagulant and Anticardiolipin antibodies. •Homocysteine -Elevated levels have been shown to increase RR of VTE – 2.5 fold -Prevalence in patients with VTE ~ 10% |
|
|
Disseminated Intravascular Coagulation: Definition
|
Disseminated Intravascular Coagulation
Definition: Abnormal activation of the coagulation system leading to excess thrombin formation (another more descriptive term is Consumptive Thrombohemorrhagic disorder). Pathology: In DIC, thrombin is abnormally activated, and subsequently consumes other pro- and anticoagulant proteins. Can present as clotting or bleeding (or both). Can be an acute process or can be chronic. THINK: DICT - DIC, Thrombin |
|
|
Disseminated Intravascular Coagulation: Pathology
|
Disseminated Intravascular Coagulation: Pathology
Pathology: In DIC, thrombin is abnormally activated, and subsequently consumes other pro- and anticoagulant proteins. Can present as clotting or bleeding (or both). Can be an acute process or can be chronic. Etiology 1) Infections (endotoxin mediated – exposure of free tissue factor) –Bacterial (eg., Meningococcus) 2) Malignancies (Expression of tissue factor/ blood vessel wall damage) –Solid tumors(eg, prostate cancer) –Acute Leukemias(Acute Promyelocytic Leukemia- increased fibrinolysis) 3) Tissue damage (release of tissue factor/ endothelial damage) –Trauma (especially brain injury) –Burns 4) Vascular disorders (Vessel injury/endothelial damage) –Aortic aneurysm 5) Immunologic disorders (cytokine release) –Acute hemolytic transfusion reactions -Anaphylaxis 6) Direct enzyme activation (direct activation of coagulation) –Snake venom 7) Obstetrical complications (exposure of tissue factor) –Amniotic fluid embolism –Retained dead fetus |
|
|
Disseminated Intravascular Coagulation: Diagnosis
|
Disseminated Intravascular Coagulation: Diagnosis
Diagnosis – ultimately a clinical diagnosis, with support from laboratory analysis Screening tests – •Platelet count – Most sensitive, but not specific •D-Dimer – sensitive, not specific •Protime – elevated ~ 75% of the time (not sensitive) •aPTT – elevated ~ 60% of the time (not sensitive) •Fibrinogen -very specific – if no underlying liver disease, but not sensitive |
|
|
What are the clotting factors in the intrinsic, extrinsic, and common pathways?
|
Intrinsic = 8, 9,11
Extrinsic = 7 Common = 2, 5, 10 |
|
|
Increased Prothrombin time means that there's a problem with the _________ pathway.
|
Increased Prothrombin time means that there's a problem with the extrinsic pathway.
THINK: PET - PT, Extrinsic |
|
|
Increased Partial Thromboplastin Time means that there's a problem with the _________ pathway.
|
Increased Partial Thromboplastin Time means that there's a problem with the intrinsic pathway.
THINK: PITT - PTT, Intrinsic |
|
|
When do you do a Mixing Study?
|
You do a mixing study any time you have a prolonger PT or PTT.
What do you do? You mix 50% of the patients blood with 50% of normal blood. If the clotting time corrects, then this means that there's a clotting factor deficiency. If the clotting time is NOT corrected, this means that something in the blood in inhibiting the clotting from occurring. There's a factor inhibitor) |
|
|
What does Von Willebrand Factor do?
|
Von Willebrand Factor = velcro and a bodyguard.
Velcro- VWF is present in the sub-endotherlial layer of blood vessels. Therefore, when the endothelium of a BV is damaged, VWF is exposed. If you think of the wall of the BV as a smooth tiled floor, when some of these tiles come up, they exposed the velcro underneath. So, if you bounce a ball (the platelet) off the the floor, if it hit the velcro, then it stick. Therefore,VWF mediated the adhesion of platelets to the sub-endothelium via the GP Ib on platelets. Bodyguard - Factor VIII is a pretty wimpy factor that would get cleared from the blood rather easily of not for VWF. VWF is the bodygrad of Factor VIII and it bind FVIII with high affinity, acting as a carrier and protector. It increases the half life of FVIII. So, decreased VWF, mean decreased FVIII - bleeding disorder. |
|
|
How does aspirin work?
|
There are several platelet agonists that help plateles aggregate:
1. Thromboxane A2 2. Thrombin Aspirin inhibits cyclooxygenase. Cyclooxygenase is responsible for making thromboxane A2. Therefore, aspirin ultimately leads to decreased thromboxane A2 and therefore less platelet aggregation. |
|
|
How does fibrinogen work?
|
Fibrinogen connects the GP IIb/GP IIIa receptors on platelets which connects the platelets = aggregation.
|
|
|
TTP vs HUS
|
Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome
BOTH TTP and HUS are: 1.Thrombotic microangiopathies 2, Characterized by MAHA (microangiopathic hemolytic anemia) and thrombocytopenia 3. Associated with microthrombi Incidence of 3.7 cases/100,000 people More common in females More common in adults Cause: Problems with ADAMTS 13. When an endothelial cell wall is damaged, a Wiebel Palade Body within the endotherlial cell relseases VWF as a very large molecule. A protein called ADAMTS 13 cuts this VFW in half, for normal function. But, if ADAMTS 13 isn't present, or if it is deficient, then the VWF stay huge. This huge VWF bind platelets, like it normally does, but because of its size, it binds to too many platelts and clots for. These clots of platelets are sharp, so as RBC go by it, they get torn/ripped apart and you get Microangiopathic hemolytic anemia. These clots can also obstruct blood vessels and can lead to kidney problems, and it the clot get to the brain, there can be ischemia in the CNS, causing neurologic symptoms. Familial – congenital deficiency of ADAMTS-13 Acquired – probably most cases autoimmune (you may get an Ab against ADAMTS -13) TTP - Diagnosis Pentad (only found ~50% of time) CNS symptoms – 60 –70% Renal dysfunction – 50% Anemia, MAHA Fever – 25 – 60% Thrombocytopenia Y – Why is happens is still unclear Idiopathic Drugs – Ticlopidine, Clopidogrel, Quinine Pregnancy Malignancy HIV Lab diagnosis MAHA (microangiopathic hemolytic anemia) Thrombocytopenia Elevated Retic count - because increased reticulocytes means that the body is trying to make new cells. LDH – often markedly high Creatinine and U/A - You have to check the urine because of TTP's affects on the kidneys. If female of child-bearing age, then pregnancy test - Why? because pregnancy may have been the cause of the TTP HUS: More common in children (especially < 5 years) Equal incidence - male/female Fever, CNS symptoms very rare Most commonly associated with infection Typically, no deficiency in ADAMTS-13 More often endothelial damage precipitating cause Damage of endothelium exposes ultra- large VWF molecules HUS - Etiology Infection – most common E. Coli O157:H7 - ? Antibiotic treatment increases risk for HUS Shigella Medications Mitomycin C Cyclosporine A Familial HUS - Diagnosis Triad MAHA Thrombocytopenia Renal dysfunction Labs – CBC, LDH, Creatinine Stool cultures |
|
|
What is the disease process of HUS?
|
HUS (Hemolytic Uric Syndrome)
A child gets infected by either E. coli O157:H7 or Shigella. Both of these bacteria release toxins. These toxins destroy the endothelium, causing the large VWF that has not been cut by ADAMTS-13 yet. Son, like in TTP, VWF binds to the platelets and there's abnormal clotting. These clots are sharp, leading to the MAHA and can block blood vessels to the kidneys causing renal dysfunction. The third feature of HUS is thrombocytopenia. HUS Triad: 1. MAHA 2. Thrombocytopenia 3. Renal dysfunction |
|
|
What inhibits VIIa
|
Tissue factor pathway inhibitor (TFPI)
|
|
|
Antithrombin
|
Antithrombin
Activity markedly increased by Heparin Inhibits IIa, IXa, Xa, XIa Heterozygote prevalence General population – 0.02-0.04%* Patients with VTE – 1% 5-25 fold increase in relative risk of VTE |
|
|
Protein C
|
Protein C
Activated by Thrombin:Thrombomodulin complex Needs cofactor Protein S for full activity Vitamin K dependent enzyme Inhibits Factors Va and VIIIa Heterozygote prevalence General population - 0.2-0.3%* Patients with VTE – 3-5% Homozygotes - very rare 7-10 fold increase in RR of VTE |
|
|
Protein S
|
Protein S
The cofactor for Protein C Vitamin K dependent Two forms - bound and free - only free Protein S is active Heterozygote prevalence General population - ?????? Patients with VTE – 3-5% Homozygotes – very rare RR from 2-10 fold increase of VTE |
|
|
Factor V Leiden
|
Factor V Leiden is a mutation in the gene that encodes for Factor V. This mutation makes Factor V resistant to the activated form of Protein C and therefore this Factor V Leiden mutation cause a disease call Activated Protein C Resistance (APC).
Usually, Protein C inhibits FV by "biting off" one of it's arms. This inactivate it. But with this mutation, Proteinc C can't recognize the bite sites in the arm of FV, so it can't bite off the arm to inhibit FV and people with this mutation have a resistance to Activated Protein C, hence the name Activated Protein C Resistance (APC). APC does increase you risk of clotting, but not significantly. Oral contraceptives increase you risk by 6-8 times, but APC only increases your risk for clot by 4 times. You can go you whole life with APC and NOT have any clotting problems. |
|
|
Prothrombin 20210A Mutation
|
Prothrombin 20210A Mutation
A G to A substitution at position 20210 in the prothrombin gene is associated with increased levels of prothrombin in the circulation Heterozygote prevalence European ethnic populations - 2% Other ethnic groups - < 1% VTE patients of European descent – 5% 2-3 fold increase in RR of VTE |
|
|
Acquired Thrombophilic States
|
Acquired Thrombophilic States
1. APLA syndrome 2. Hyperhomocysteinemia |
|
|
When can you acquire APLA syndrome?
|
APLA syndrome
Pregnancy Trauma Surgery Immobilization Age |
|
|
When can you acquire Hyperhomocysteinemia/
|
Hyperhomocysteinemia
Myeloproliferative disorders Nephrotic syndrome (kidneys pour out ProC and ProS) Estrogen Malignancy |
|
|
Homocysteine
|
Homocysteine
Elevated levels have been shown to increase RR of VTE – 2.5 fold Prevalence in patients with VTE ~ 10% |
|
|
Anti-Phospholipid Antibodies (APLA)
|
Anti-Phospholipid Antibodies (APLA)
Autoantibodies against phospholipid-protein complexes that promotes coagulation Associated with venous and arterial thromboses and recurrent miscarriages Can be transient Account for 10-15% of idiopathic VTE’s 2 Types of APLA: 1. Lupus Anticoagulant (LA) - BAD NAME because this is a pro-coagulant Ab that's NOT found in people with Lupus. 2. “Anticardiolipin” antibodies (ACA) |
|
|
Tissue factor
|
Tissue factor is necessary for the initiation of thrombin formation from the zymogen prothrombin.
Therefore, any time the body is exposed to pr releases TF, this will cause in increase in thrombin. Excess thrombin can cause DIC because of thrombin's ability to consume both coagulants and anti-coagulants. |
|
|
How does a blood clot form, from start to finish?
|
There's injury to a blood vessel. Cells within the endothelium called Wiebel Palade Bodies release Von Willebrand Factor. VWF binds to platelets on their GIb receptor. Injury and the release of tissue factor also starts the coagulation cascade. This cascade, through the aid of thrombin, results in the production of fibrin. Fibrin layers are placed over the area that has already been plugged up by the platelets. The fibrin layers are reinforcement for the plug.
|
|
|
Primary versus Secondary Hemostasis:
|
Primary versus Secondary Hemostasis:
Primary Hemostasis involves the platelet plug and VWF. Secondary Hemostasis involves the blood clotting factors. |
|
|
What can be found in a peripheral blood smear to give clues that the spleen is either absent or not working properly?
|
1. Nucleated RBCs
2. Howell-Jolly Bodies - remnant of a nucleus in a RBC |
