Clotting disorders/anticoagulation Flashcards
Thrombophilia
general
A condition that increases a patient’s risk of thrombosis
THrombophilia
aquired risk factors
Advancing age
Prior Thrombosis
Immobilization
Major surgery
Malignancy
Estrogens
Antiphospholipid antibody syndrome
Myeloproliferative Disorders
Heparin-induced thrombocytopenia (HIT)
Prolonged air travel
thrombophilia
Inherited RF
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Factor V Leiden mutation
Prothrombin gene mutation
thrombophilia
HIGH Risk Classification & Management
High Risk needs indefinite anticoagulation
- 2 or more spontaneous events
- 1 spontaneous life-threatening event (near-fatal pulmonary embolus, cerebral, mesenteric, portal vein thrombosis)
- 1 spontaneous event in association with antiphospholipid antibody syndrome, antithrombin deficiency, or more than 1 genetic defect
thrombophilia
MODERATE Risk Classification & Management
Moderate Risk needs vigorous prophylaxis in high-risk settings
1 event with a known provocative stimulus
Asymptomatic
Factor V Leiden Mutation thrombophilia
general
Most common hereditary thrombophilia in the US
Autosomal dominant - 3% of the population
White ~ 5%
Latinx ~2%
- Inability of protein C to inactivate factor V leading to hypercoagulable state (2.2-fold increased risk for VTE)
- “Leiden” is a city in Holland where the abnormal gene was discovered
Factor V Leiden Mutation thrombophilia
Dx
Laboratory testing
Factor V Leiden mutation analysis
Factor V Leiden Mutation thrombophilia
Factor V Leiden
Factor V Leiden
Activated Factor V (Va) combines with activated Factor X (Xa) to form Prothrombin Activator
Factor Va then degraded by aPC
Specific point mutation (Arg506Gln) on Factor V
Eliminates cleavage site that promotes Factor V degradation
Factor V breakdown products are used as cofactors for Factor Va & VIIIa degradation via aPC
Remember aPC is activated Protein C, an anticoagulant
some reptition here
Heterozygous Factor V Leiden
Clin man
Clinical Manifestations:
Increased risk of VTE (about 4X greater than general population) (VenousThromboEmbolism)
Arterial thrombosis – data are mixed and FVL likely has a small impact on risk
Obstetrics -may play a role in some cases of unexplained recurrent late pregnancy loss
Majority of patients are asymptomatic (95% never have VTE)
For those with VTE:
Low risk of recurrence in heterozygous state
Should not alter decision making regarding duration of anticoagulation
Homozygous Factor V Leiden
risk of VTE
Increased risk of VTE (about 25-50X greater than general population)
Prothrombin G20210A Mutation
general
2nd most common inherited thrombophilia
Predominantly identified in white population
~2% of general population
Substitution of adenine for guanine at position 20210 in a non-coding region of the prothrombin (Factor II) gene
Heterozygotes for the G20210A mutation have ~30% higher plasma prothrombin levels than controls
Prothrombin G20210A Mutation
Risk of VTE
Clinical Manifestations:
Increased risk of VTE (about 3-4X greater than general population)
Low risk of VTE recurrence in heterozygous state
Should not alter duration of anticoagulation
Antithrombin III Deficiency
general
Also known as Antithrombin III
Antithrombin III is a circulating plasma protein that prevents clots from forming abnormally
Inhibits coagulation by irreversibly binding the thrombogenic proteins thrombin (IIa), IXa, Xa, XIa and XIIa
Antithrombin III Deficiency
Prevents binding with heparin to reduce the presence of thrombin
No antithrombin III = ?
antithrombin III thrombophilia
Dx testing
Testing for this disorder via AT-heparin cofactor assay
Measures the ability of heparin to inhibit factor Xa or IIa (prevent clotting)
Since AT is needed for heparin to do this, lack of inhibition indicates lack of AT
Protein C Deficiency
General
For protein C to work protein S must be available
Protein C deficiency may cause thrombosis when levels ≤50%
Vitamin K dependent glycoprotein produced in the liver
In the activation of protein C, thrombin binds to thrombomodulin
This complex then converts protein C to activated protein C (APC), which degrades factors Va and VIIIa, limiting thrombin production
Inherited
Acquired
Surgery, trauma, pregnancy, OCP, liver or renal failure, DIC,or warfarin use
Protein C (PC) Deficiency
more general and Dx
Protein S is cofactor
Reduced degradation of Factor V/Va and VIII/VIIIa
If factors Va and VIIIa stick around longer, what is the consequence?
Testing for this disorder by using enzymatic assays with chromogenic substrates
Can also use aPTT-based clotting assays or factor Xa-based clotting assays, but these do not perform as well
Protein S
general
Functions predominantly as cofactor for action of anticoagulant activated protein C
Protein S participates as part of one mechanism of controlling clot formation
Inherited Protein S deficiency is an autosomal dominant disorder
Thrombosis when levels ≤50%
Functional PS activity may be decreased in vitamin K deficiency, warfarin, liver disease
Increased PS consumption occurs in acute thrombosis, DIC, MPD, sickle cell disease
Antiphospholipid Antibody Syndrome
general
Persistent presence of antiphospholipid antibodies or lupus anticoagulant for ≥ 12 weeks in context with an acute thrombotic event
Venous or arterial thrombosis
Recurrent pregnancy loss < 10 week gestation
Premature delivery or fetal demise >10 week gestation
Antiphospholipid Antibody Syndrome
labs
Lupus anticoagulant
Anticardiolipin antibodies
Anti-β2 glycoprotein
DRVVT- venom activates F. X directly; prolonged by LAC’s
APTT- Usually prolonged, does not correct in 1:1 mix
Prothrombin Time- seldom very prolonged
Antiphospholipid antibody Syndrome
Tx
Indefinite anticoagulation for patients with definitive APS and thrombosis
Risk of thrombosis is 50% at 2 years after discontinuation
Warfarin (coumadin)
Warfarin and other Vitamin K Antagonists
Inhibit the synthesis of vitamin K-dependent clotting factors, which include:
Factors II, VII, IX, and X
(1972)
Anticoagulant proteins C and S
Warfarin (Coumadin)
contraindications
Contraindications:
Pregnancy
Avoid with liver disease
Dosing: Typically start at 5mg PO daily
Monitored with PT/INR levels
Every 3-5 days –> Weekly –> Monthly
INR target of 2.0 to 3.0
3 days to reflect dose changes
warfarin
Diagnosing hypercoagulable states in patients receiving warfarin
Warfarin inhibits synthesis of all Vitamin K dependent proteins, including Protein C and S
Warfarin initially decreases protein C levels faster than the other coagulation factors
Paradoxically increases blood’s tendency to coagulate when treatment is first begun –> warfarin necrosis
Why we start additional anticoagulant first
Warfarin necrosis more frequent in patients with Protein C and S deficiency
Recognize that many dietary items and drugs can interact with vitamin K antagonists
Initiation and discontinuation of medications
Antibiotics
Anti-convulsants
Anti-fungals
Antacids
Febrile illnesses
Gastroenteritis
Liver disease
Vitamin K containing foods
Enteral feeds
Mango
Avocado
Fish Oil
Soy milk
Grapefruit
Warfarin Reversal
Vitamin K 2-5 mg PO, SQ or IV
IV slow infusion due to anaphylaxis
Fresh Frozen Plasma
Stops bleeding but does not completely reverse VKAs
Prothrombin Complex Concentrates
Contain many Vitamin K dependent proteins at high concentration
Infusion/Injection Anticoagulants
Unfractionated heparin infusion/injection
Low molecular weight heparin injections
Fondaparinux injections
Unfractionated Heparin
general
Naturally occurring anticoagulant
Binds reversibly to antithrombin
Increases antithrombin’s inhibition of thrombin and Factor Xa
Dosing: Bolus followed by continuous infusion
PTT (target range 65-80 seconds or 1.5-2.5X baseline)
Sensitive to improper collection, anemia, thrombocytopenia, factor deficiencies, lupus anticoagulant, age
Monitor every 4-6 hours after dose change and daily
A note about Heparin
Low dose:
Inactivates factor Xa and inhibits conversion of prothrombin to thrombin
High dose:
Inactivates factors IX, X, XI, and XII and thrombin and inhibits conversion of fibrinogen to fibrin
Also inhibits activation of factor VIII
LMWH
general
Binds to and accelerates the activity of AT, but with a preferential and longer-lasting effect on Xa
Less able to inhibit thrombin and bind to other plasma proteins
Brand Names: Lovenox
Another common one is Fragmin (Dalteparin) but dosed differently
Dosing: 1 mg/kg SC BID or 1.5mg/kg SC daily
No monitoring bloodwork for dosing needed
Peak anti-Xa level is 2 to 6 hours after administration
Obtain level 4-6 hours after dose
Goal 0.5 to 1.0 U/ml for treatment
Fondaparinux (Arixtra)
general
Binds and enhances activity of AT by 300-fold
Does not bind to other plasma proteins
No direct effect on thrombin
Dosing: Weight based. Most commonly 7.5mg SC once daily
Therapeutic dose lab monitoring not required
Anti-Xa activity can be obtained
Direct Thrombin Inhibitor
Argatroban
Reversibly binds to the active thrombin site of free and clot-associated thrombin. Inhibits fibrin formation; activation of coagulation factors V, VIII, and XIII; activation of protein C; and platelet aggregation.
Onset: immediate
Use: HIT, Heart catheterization
Dosing: Weight based/min infusion- Dialyzable
May be a combined effect on the INR when argatroban is used with warfarin
Loading doses of warfarin should not be used
The ACP suggests monitoring chromogenic factor X assay
Adverse effects: Hypotension, bleeding, fever
Caution with hepatic impairment
Dabigatran (Pradaxa)
use, contraindications, adverse effects
Use: VTE, Afib
Dosing (VTE): 150 mg twice daily
Avoid in moderate to severe renal impairment
Adverse effects: Hemorrhage, abdominal pain, dyspepsia
Direct Oral Anticoagulants
Factor Xa inhibitors
Inhibits platelet activation and fibrin clot formation via inhibition of free and clot-bound factor Xa
Comparable efficacy to VKA in adults, but with significantly lower risk of bleeding
Reversal agents FDA approved
A prolonged PT suggests clinically relevant serum concentrations are present, but normal PT and aPTT values cannot rule out the presence. Anti-factor Xa activity can be ordered.
Factor Xa Inhibitors more
Pregnancy: Insufficient data
Monitoring: CBC, aPTT, PT, serum creatinine, and liver function tests prior to initiation and at least annually
Surgeries which raise the pH of the stomach (Roux-en-Y gastric bypass) or decrease small intestine may decrease absorption of edoxaban
Not recommended for patients with triple-positive antiphospholipid syndromes (lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I)
May have increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy
Avoid removal of epidural or intrathecal catheter for at least 12 hours following last edoxaban dose and avoid next dose for at least 2 hours following catheter removal due to risk of spinal or epidural hematomas.
Savaysa (Edoxaban)
Use: DVT/PE, Afib, approved for cancer patients
Dosage (VTE):
Patient weight >60 kg: 60 mg once daily
Patient weight ≤60 kg: 30 mg once daily
Use is not recommended in mod-severe hepatic and severe renal impairment
Adverse effects: Hemorrhage
ELIQUIS (Apixaban)
Use: VTE, Afib, prophylaxis, approved for cancer patients
Dosage (VTE): 10 mg twice daily for 7 days followed by 5 mg twice daily
Avoid in moderate to severe liver impairment
Adverse effects: Hemorrhage
Xarelto (Rivaroxaban)
Use: DVT/PE (may use in active cancer), Afib, CAD, PAD, SVT
Dosing (VTE): 15 mg twice daily with food for 21 days followed by 20 mg once daily with food
Avoid in moderate to severe liver and severe renal impairment
Adverse effects: Hemorrhage, gastroenteritis, vomiting
May contain lactose
Thrombolytic Therapy
general
Activate plasminogen to form plasmin, which accelerates the lysis of thrombi
Rapid clot lysis provides symptom relief and restores limb perfusion
Catheter directed therapy performed by surgeon or interventional radiologist
May place IVC filter at same time
Drug: Tissue plasminogen activator (tPA)
Dose: 0.5 to 1 mg/hour
Anticoagulant therapy (typically unfractionated heparin) is generally continued before, during, and after the thrombolytic infusion
Assess clinically for pulmonary embolism and any changes in neurologic or mental status
Adverse effect: Bleeding <2%
Contraindications to Thrombolysis
Active major bleeding
Significant potential for uncontrolled local bleeding
Surgery within preceding 10 days
Neurosurgery, including spinal surgery, within preceding 60 days
Seizures within 48 hours
Sepsis
Elevated serum creatinine
Uncontrolled hypertension
Contrast allergy
Types of Thrombolysis
Tissue plasminogen activator (tPA) is the most used thrombolytic agent
Catheter-Directed Thrombolysis
Placement of large-bore catheter into the vein affected by the DVT to allow slow, direct infusion of thrombolytic agent into the thrombus
Systemic Thrombolysis
Hirudotherapy
Medical leaches (hirudinea)
Use dates to ancient Greece and Egypt
Bloodletting to prevent disease and cure illness
Medical leach farms
Anesthetized and disposed off after one use
Current FDA approved use
Tissue graft venous congestion
