Coagulopathies Flashcards
1
Q
Common Bleeding Disorders
A
1) Hemophilia
2) von Willebrand’s Disease (vWD)
3) Ideopathic Thrombocytopenia Purpura (ITP)
2
Q
Hemophilia Facts: Genetic/Ethnic
A
- Congenital bleeding disorders caused by deficiency or absence of clotting factors
- – Hemophilia A: Factor VIII
- – Hemophilia B: Factor IX
- X-linked: Inherited by male offspring from carrier mothers
- Female offspring of males w/hemophilia are “Obligatory carriers”
- No racial differences
3
Q
Hemophilia Facts: Severity
A
- Because factors VIII and IX are required for thrombin formation, hemophilia can cause prolonged, often spontaneous bleeding
- Mild: 5-40% of normal factor present; usually only bleed with significant trauma
- Moderate: 1-5% of normal factor present; Usually do not bleed spontaneously
- Severe: <1% of normal factor present; often have spontaneous bleeds
4
Q
Hemophilia: Diagnosis
A
- Factor assays; bleeding patterns; family history
- aPTT: prolonged in hemophilia (assess factors VIII and IX)
- Usually diagnosed within childhood
- – 95% by age 15
- – ~50% will have severe deficiency if there is reason to diagnose early in childhood
- Screen at birth, males with family Hx
5
Q
Hemophilia: Presentation
A
- Neonates: Intracranial hemorrhage; prolonged bleeding from circumcision
- Infants: Excessive bruising in soft tissues
- Older children and adults: spontaneous bleeding in joints
- – Hemarthrosis: ~70% of joint bleeds (knees, ankles, elbows most common)
- – Bleeds may also occur in CNS, GI tract, soft tissues and muscles
6
Q
Hemophilia: Long-term complications
A
- Hemarthropathy:
- – Bleeding into joints leads to an inflammatory process, causing permanent damage
- – Contractures
- – Nerve damage
7
Q
Hemophilia: Treatment (Non-pharmacologic)
A
- Focused of preventing or stopping bleeding episodes
- Hemarthrosis
- – RICE; Splinting, casts, crutches to allow joint or muscle rest after bleeding episode; Ice to slow down inflammatory process; PT once pain and inflammation resolve
8
Q
Hemophilia: Treatment (Pharmacologic)
A
- Desmopressin: Treats acute bleeding by increasing factor VIII
- Antifibrinolytics:
- – Tranexamic acid and aminocaproic acid
- – Treats acute bleeding by stabilizing fibrin clot
- – Useful in mucosal bleeds and dental procedures
9
Q
Hemophilia: Factor Replacement
A
- Treatment of of choice for acute bleeding episodes in severe hemophilia
- Dose depends on location and severity of bleeding
- Goal is to achieve hemostasis by adequately replacing factors
- – 40-60% of normal for joint and muscle bleeds
- – 80-100% of normal for iliopsoasmuscle, throat or neck, CNS, or GI bleeding
10
Q
Safety of Hemophilia Treatment
A
- 1980’s: Exposure to HIV and HCV through contaminated plasma-derived factors
- Now, virus reduction is used in factor collection, including nanofiltration, vapor heat, dry heat, pasteurization, solvent/detergent treatment
- Development of antibodies or inhibitors to factors
- – Does not promote bleeding, but makes subsequent bleeding episodes difficult to treat
11
Q
von Willebrand’s Disease Facts
A
- Autosomal dominant bleeding disorder
- Deficiency or dysfunction of von Willebrand factor (vWf)
- vWf has two roles:
1) Facilitates initial platelet plug at vascular injury
2) Carrier of factor VIII, preventing its degradation
12
Q
vWD: Subtypes
A
I) Levels of vWf are decreased 5-30%; most common subtype
II) Levels of vWf are normal, but dysfunctional
— Subtypes I and II are usually present with mild bleeding after procedures, mucosal bleeding, menorrhagia, and nose bleeds
III) Near or complete absence of vWf; bleeding similar to hemophilia and can be life threatening
13
Q
vWD: Labs
A
- Reduced plasma levels of vWf activity
- Reduced factor VIII activity
- Reduced vWf antigen levels
- Prolonged bleeding time
- ** NL levels do NOT exclude vWD
- ** PLT, PT, and PTT are all NL in vWD
14
Q
vWD: Acute treatment
A
- DDAVP: synthetic vasopressin that increases vWF and factor VIII (INEFFECTIVE in subtype III)
- If DDAVP fails:
- FFP
- Cryoprecipitate
- Concentrated factor VIII, fibrinogen, or fibronectin
- Subtype III: Concentrated factor VIII/vWF are available in larger institutions
15
Q
Ideopathic Thrombocytic Purpura (ITP): Facts
A
- Low platelet count that is not related to bone marrow suppression
- Common: Adults 66:1,000,000; Children 50:1,000,000
- Generally presents b/n 2-9yo and 20-50yo
16
Q
ITP: Children
A
- 2-3wk after viral illness
- Rapid drop in PLT
- Most resolve within 6mo
- Usually develops petechia and/or purpura
17
Q
ITP: Adults
A
- May have no prodromal illness
- Slow drop in PLT
- Tends to be chronic
18
Q
ITP: S/S
A
- Purpura (easy/excessive bruising)
- Petechiae (superficial bleeding)
- Prolonged bleeding from trauma
- Epistaxis
- Gum bleedings
- Hematuria, melena
- Menorrhagia
19
Q
ITP: Treatment
A
- PLT >20K with no S/S: No Tx
- Symptomatic patients and those at risk should receive immunosuppression (i.e. athletes)
- Corticosteroids: prednisone or prednisolone 1-2mg/kg/day
- – Only about 15% will have complete remission
- IVIG: If PLT <10K), continuous steroids required to maintain PLT levels
20
Q
Clotting Disorders: Thrombophilia
A
- Familial
- Factor V Leiden
- Protein C deficiency
- Protein S deficiency
- Anti-thrombin deficiency
- Prothrombin 20210A mutations
- Acquired
- Antiphopholipid antibody syndrome
- Lupus inhibitor
21
Q
Factor V Leiden Facts
A
- Inherited mutation in factor V tht causes resistance to activated protein C (APC)
- APC inactivates factors V and VIII, which are crucial in forming thrombin
- Some form on FVL is present in ~30% of those who develop an embolism
- 5% in US are heterozygous (carriers)
- Risk is 7x greater than in noncarriers
- 1 in 5K are homozygous for FVL
- Risk of embolism is 80x greater than in those without trait
22
Q
Antiphopholipid Antibody Syndrome (APLS)
A
- Antibodies to phopholipid complexes: Lupus anticoagulant, anticardiolipin antibodies, anti-beta-2 glycoprotein antibodies
- Characterized by arterial and venous embolism and recurrent pregnancy loss
- Up to 28% with APLS have recurrent thromboses, increasing mortality
23
Q
Venous Thromboembolism (VTE)
A
- Any embolic event in the vascular system
- DVT: Upper or lower extermities
- PE: Pulmonary embolism
- Other systemic embolism: Splenic vein thrombosis, superior mesenteric vein thrombosis
24
Q
Risk Factors for VTE: Reversible
A
- Immobility
- Hormone use
- Trauma, especially long bone FX, hip, pelvis, or multiple Fx
- Pregnancy and immediate post-partum
- CVC
- Prolonged travel
25
Risk Factors for VTE: Irreversible
- Spinal cord injury/paralysis
- Malignancy
- CHF
- Varicose veins
- Respiratory failure
- Prior VTE
- Age >40
- Hypercoagulable state
26
VTE: Management
- Anticoagulation:
* Prevents extension of clot
* Prevents migration of clot
* Prevents development of clot in high risk patients: Certain orthopedic procedures; Hx of recurrent clot; A-Fib; mechanical heart valve
27
VTE: Anticoagulant Options
- ASA
- Vitamin K Antagonists: Warfarin (a-fib, VTE, mechanical valve
- Direct Thrombin inhibitors: Dabigatran (Pradaxa) ( A-fib only)
- Direct Factor Xa inhibitors: Apixiban (Eliquis) (A-fib only); rivroxaban (Xarelto) (A-fib, VTE)
- Heparin & low molecular weight heparin (LMWH): Enoxaparin (usually bridging therapy or cancer associated clots)
28
Treating VTE: PE or DVT
- DVT with reversible risk factor: Duration of anticoagulation is 3mo
- PE with reversible risk factor: Duration of anticoagulation is 6mo
- Either condition unprovoked: Consider lifelong anticoagulation; hypercoagulable workup is warranted
29
Thrombophilia workup
- Activated protein C
- Factor V Leiden
- Prothrombin (Factor II) mutation
- Antithrombin functional assay
- Protein C functional Assay (off warfarin)
- Protein S functional assay (off warfarin)
- Antiphopholipid antibody
- Homocysteine level
- Factor VIII Assay
30
Anticoagulation recommendations in hypercoagulable patients
- Anticoagulation for hypercoagulable state without VTE is NOT recommended
- If recurrent VTE and hypercoagulable state, long-term anticoagulation is recommended
* APLA, FVL, Protein C or S deficiency
31
Warfarin: Facts
- Vitamin K antagonist (VKA)
- Inhibits formation of functional vitamin K dependent clotting factors in the liver: II (prothrombin), VII, IX, X
- Inhibits protein C and S, which will prevent extensive clot formation
- Hepatic clearance: CYP 450 2C9, 1A2, 3A4
* ** DRUG-DRUG Interactions
32
Warfarin: Pharmacodynamics
- 100% absorbed from oral administration, peak concentration in 4hr
- Onset of anticoagulant activity in 3-4d: takes up to 60hr for existing clotting factors to degrade
- Duration of singe dose is 2-5d: new clotting factors must be reformed after discontinuation
- Crosses placenta and has SEVERE teratogenic effects; does NOT cross into breast milk
- Half-life of 40hr
33
Warfarin: Points to remember
- Warfarin is monitored by INR
- Effects on INR seen in 8-12hr after initial dose due to depletion of factor VII, however, full effect of single dose not appreciated for several days
- Warfarin does not impact existing clotting factors, only newly produced factors
- Narrow therapeutic index
- Color-coded based on tablet strength
- Coumadin is round; warfarin is oval
34
Warfarin Contraindications: Absolute
- recent hemorrhagic stroke
- Risk for active major bleeding
- Recent trauma or major surgery
- Immediately post-op CNS surgery
- CNS tumors with major bleeding risk
- Presence of CNS catheter or aneurysm
35
Warfarin Contraindications: Relative
- Cognitive impairment
- Severe psychiatric illness
- Alcoholism
- Severe liver or kidney disease
- High risk for falls
- Documented medical nonadherence should be considered
36
INR Goals for Warfarin Therapy
- 2-3
* A-fib; treatment of VTE/PE; Prevention of VTE in high risk surgery; tissue heart valves; mechanical aortic valves
- 2.5-3.5
* Mechanical mitral valve; mechanical aortic valve with additional risk factor (LA enlargement); Prevention of recurrent MI; Hx of VTE with INR of 2-3
37
Initiation of Warfarin: Starting Doses
- Typically starting dose is 5mg daily
* ** 2.5mg in the elderly, those with CHF, hyperthyroidism, malnutrition, liver dysfunction
* ** Younger, larger patients may require higher starting doses of 10mg (especially athletes)
- Dose adjustments should be made by percentage of WEEKLY dose, generally no more than 5-20% adjustment
38
Initiation of Warfarin: Monitoring
- Monitor INR at baseline and a minimum of 2-3x/wk for 1-2wk
- After 1-2wk, increase follow-up interval to 1wk
- Twice monthly monitoring until at least 2 INR therapeutic at STEADY STATE (same dose for 2wk)
- Goal is INR monitoring q4-12wk
39
Rivaroxaban (Xarelto): Facts
- Direct factor Xa inhibitor
- Inhibits conversion of prothrombin to thrombin
* that disrupts the clotting cascade
- 2/3 metabolized hepatically; remainder renally excreted unchanged
* Safety in patients with renal insufficiency or failure is not established
- Half-life of 7-11hr
- Monitoring: None
40
Rivaroxaban: Uses
- Used for CVA prophylaxis in nonvalvular a-fib
- Used for treatment of DVT or PE
- Rivaroxaban is not inferior to warfarin in terms of prevention of CVA or systemic embolism
- Causes less fatal bleeding and ICH than Warfarin
- No difference in non-fatal bleeding with rivaroxaban compared to warfarin
41
Rivaroxaban: Dosing
- Adult dose: 20mg q day with evening meal
- Dose adjustments:
* CLcr >50mL/min: No adjustment necessary
* CLcr 15-50mL/min: 15mg QD with evening meal
* CLcr <15mL/min: Avoid use
* ESRD requiring HD: Avoid use
42
Considerations with newer agents: Advantages
* Predictable patient response: Can prescribe fixed dose
* Once-daily dosing (Some)
* No monitoring
* Few known drug interactions
* Short half-life
43
Considerations with newer agents: Disadvantages
* No antidote
* Drug-drug interactions
* No monitoring
* Renal dosing
* Expensive
* Lack of evidence if dose is missed
* Multiple daily doses
44
Initiation of Anticoagulation in VTE
Heparin or LMWH is used WITH warfarin to provide anticoagulation until therapeutic INR is achieved
- LMWH is superior to unfractionated heparin in preventing progression of VTE disease and in efficacy and ease of administration; given SQ
* Inhibits Factor Xa and factor IIa: exerts rapid effect
* Half-life 7hr
* Available in prefilled syringes in multiple strengths (30, 40, 60, 80, 100, 120, 150mg)
45
LMWH in Treatment of VTE
- Treatment doses:
* 1mg/kg BID or 1.5mg/kg daily started simultaneously with warfarin
* Given until INR is therapeutic (2-3)
- Prophylactic doses:
* Are NOT weight based; NOT recommended for treatment of VTE; may be used to prevent VTE in high risk patient (hospitalized, certain orthopaedic preocedures)
- LMWH should be initiated any time that INR is below therapeutic range in 6wk period following VTE or in patient at high risk of recurrence of VTE
- LMWH should be initiated any time anticoagulation will be interrupted in the high risk patient
