Coagulation - Rajan 03.30.15 Flashcards
What is Factor V Leiden mutation?
- Normal procoagulant activity
- Inactivated slowly by activated Protein C
- INC prothrombinase activity -> failure to remove Va
- Pts also have increased VIIIa/tenase activity -> V a co-factor for VIII inactivation, but V Leiden unable to do this
- Extremely common (5-20% of Caucasian pop)
- Increased risk of venous thromboembolism; 6% of heteros devo VTE by age 65
- Can exist in combo w/other defects
What is Prothrombin G20210A?
- Mut in 3’ non-coding seq of prothrombin gene
- Mainly N. European mutation
- INC prothrombin syn (>115% of normal) - short PT
- Implicated in both arterial (stroke) and venous thrombosis: <5% heteros devo VTE by 60, and homos devo moderate thrombophilia
- Pregnancy-related thrombosis and complications
What is hyperhomocysteinemia?
- Acquired (B12, folate) or inherited
- INC homocysteine = higher atherothrombosis; OR INC dramatically when plasma homocysteine >22 umol/L
- Mechs unclear, but also increased venous thrombosis
- Interventional trials haven’t been +
What are some causes of acquired thrombophilia?
- CHF
- Inflammatory disease
- Nephrotic syndrome
- Diabetes
- MPD, TTP, DIC, HIT, PNH, antiphospholipid syndrome
- Atherosclerosis
- Surgery
- Immobilization, and many more
What are some causes of acquired antithrombin deficiency?
Pregnancy, liver disease, DIC, nephrotic syndrome, major surgery, acute thrombosis, heparin, estrogen Rx
What are some causes of acquired Protein C and S deficiencies?
- Protein C: liver disease, DIC, acute thrombosis, Warfarin
- Protein S: pregnancy, liver disease, DIC, inflammation, acute thrombosis, Warfarin, estrogens Rx
How is a platelet plug formed?
- PLATELETS attach to exposed collagen
- Aggregation of platelets causes release of chemical mediators (ADP, Thromboxane A2)
- ADP attracts more platelets
- Thromboxane A2 (powerful vasoconstrictor): that promotes aggregation & more ADP
Is gangrene a sign of bleeding?
No
A 25 year female is evaluated by you for easy bruisability. She has no h/o epistaxis or menorrhagia. Has a brother who also has easy bruising, no other family with bleeding tendency. She has her wisdom teeth extracted with no bleeding two months ago. On exam you note a high arched palate, and she is double jointed. Her Platelet count, FVIII level, von willebrand ag, von willebrand activity, PT and PTT are normal. Her likely diagnosis is:
Likely non-hematologic cause, like collagen disorder
What is ristocetin?
- Test used to diagnose von Willebrand’s disease -> abnormal agglutination if disease +
Pt. comes in with bleeding. What is your plan if platelet count is low? What if it is normal?
-
Low:
1. Bone marrow exam
2. Platelet antibodies
3. Screening tests for DIC -
Normal:
1. Bleeding time
2. Platelet aggregation studies with ADP, collagen, adrenaline, and ristocetin
3. O/special platelet tests, e.g., adhesion studies, nucleotide pool measurement
4. vWF, VIII assays
What are some causes of thrombocytopenia?
- Platelets < 150,000
- Decreased production of platelets: bone marrow failure, chemo, radiation,
- Increased destruction: immune thrombocytopenia, HIT, DIC, post-transfusion purpura, von Willebrand disease, Type 2B, hemophagocytosis
- Increased sequestration: hypersplenism
- Others: Bernard-Soulier, pseudothrombocytopenia (this mean pt has Abs to EDTA, causing aggregating)
Know these.
Good job!
What is immune thrombocytopenia?
- Children: acute, treatable; adults: chronic
-
Dx of exclusion: thrombocytopenia not due to DIC, TTP, HUS, artifact, splenic sequestration, primary bone marrow disease (i.e., to distinguish from CLL), etc.
1. No specific or sensitive test for ITP -> can order anti-platelet Abs, but discouraged b/c common
2. Increased MPV; normal PT, PTT - Usually, we do nothing for these ppl if platelet counts >50,000 bc these low numbers idiosyncratically do not prolong bleeding time
What is your differential diagnosis? How do you sort this out?
- Differential: B12, folate deficiency, hypersplenism alcohol, medications, myelodysplasia, other bone marrow pathology
-
How do you sort this out?
1. Obtain a history and examine the patient
2. Ultrasound of the abdomen (spleen size)
3. Serum B12, RBC folate
4. Bone marrow investigation
What are some tests for qualitative platelet abnormalities? KNOW how to interpret this graph.
- Bleeding time
- Platelet function analysis
- Platelet aggregation studies
What is unique about low platelet count in ITP?
- In people w/normal platelet function, bleeding time not prolonged unless platelet count <100,000/mm3
- Ppl w/ITP -> often have normal bleeding times despite very low platelet counts
- Ppl w/qualitative platelet defects, due to aspirin, uremia, or von Willebrand disease, have normal platelet counts, but prolonged bleeding times
What are the lab tests for bleeding?
- Prothrombin time (PT)/INR
- Partial thromboplastin time (PTT)
- Thrombin time
- Fibrinogen
- Factor assays
- Correction/inhibitors
Know this.
Good job!
Know this.
- Good job!
- Note: Factor VIII the only factor that goes UP in the context of liver disease
Know this one too. What is the important diagnostic feature of the mixing study?
- Lupus anticoagulant: NO CORRECTION ON MIXING STUDY
1. Having thrombocytopenia with this disease not uncommon (bleeding NOT associated with disease -> CLOTTING)
Review this.
Good job!
What are some of the major distinctions between VIII deficiency and vWF deficiency?
- VIII: X-linked, normal bleeding time, normal vWF levels, hemarthrosis and hematomas
- vWF: autosomal, prolonged bleeding time, low vWF levels, mucosal bleeding
Maybe know this?
- Type III: if vWD totally gone, VIII will be totally gone too
Know how to read this.
- Of note, in TTP, vWF is longer
- In vWF deficiency, it is shorter, or absent
What is Hemophilia A?
- 1 in 10,000 Male Births; X-Linked
- Variable Severity; Hemarthrosis Major Condition
- Just >5% of Factor VIII- mild disease, 1-5%- Moderate, <1% Severe
- Therapy with Earlier Cryoprecipitate; Majority of Adult Hemophiliacs Infected HIV
- **Mild HA; Desmopressin (DDAVP) → ↑VIII **(stimulates release of vWF from endothelial cells)
- IgG Anti-VIII Inhibitors 10% Patients
- Activated Factor IX Complex (II,IX,X,VIIa)
- Exchange Plasmapheresis
- Increased PTT
What is Hemophilia B?
- Xmas Disease; 1 in 100,000 Male Births (X linked)
- Clinically Identical to Hemophilia A
- Fresh Frozen Plasma to dilute for hemorrhage
- Antibody Inhibitors less Common
- Increased PTT
- Treatment: Factor IX Concentrate (DDAVP not effective)
- Associated with Thrombosis - Activated Impurities
What is Hemophilia C?
- Deficiency of Factor XI
- Rosenthal’s Disease
- Autosomal recessive
- Ashkenazi Jews
- PTT prolonged
- Usually mild symptoms
- Treatment: FFP
What is von Willebrand’s Disease?
- Most Common bleeding diathesis -> 1% prevalence
- Defect platelet adhesion, ↑ Bleeding time
- VWF stabilizes Factor VIII and protects it from degradation by activated protein C, and also mediates platelet adhesion
- Symptoms: mucocutaneous bleed, menorrhagia, epistaxis, bruising, surgical risk
- Treatment: DDAVP Induces vWF Release, Factor VIII concentrate (high vWF levels)
A 22y female with hashimoto thyroiditis, who is currently euthyroid, has been noted with symptomatic cholelithiasis and needs a cholecystectomy. She had wisdom teeth extraction last year with no bleeding. She has no history of epistaxis, menorrhagia or bruising. You perform a CBC, PT and PTT. Her CBC and PT are normal but PTT is prolonged at 45seconds. A mixing study is not corrected. What is the next best step:
Lupus anticoagulant testing
How does liver disease cause coagulopathy?
- Vitamin K deficiency
- Thrombocytopenia
- Decreased production of clotting factors
- Dysfibrinogenemia
- Increased fibrinolytic activity
What coagulation factors are decreased by liver disease, Vit K deficiency, and DIC?
- Liver disease: V, VII, X
- VItamin K deficiency: VII, X
- DIC: V, VII, VIII, X
How is Vitamin K involved in coagulation?
- Needed for gamma carboxylation of factors II, VII, IX, X, proteins C & S
- Warfarin inhibits vitamin K carboxylation, induces deficiency state for over a week.
- Rapid ↓Factor VII, initially ↑PT, later ↑PTT.
- Deficiency results from nutritional deficits, antibiotic use, fat malabsorption
What are the characteristics of Vitamin K deficiency?
- Mild PT prolongation: asymptomatic
1. Vitamin K, PO or SC; avoid IM, careful IV - Anticoagulant dependent patients
1. Titrate correction; response 6 - 12 (48) hours - Severe ↑PT or Symptomatic -> FFP
- Liver disease: ↓Factor synthesis, K Stores
1. Vit K often ineffective -> FFP, cryoprecipitate if low fibrinogen
