Clotting disorders/anticoagulation

Question 1

Thrombophilia

general

Answer 1

A condition that increases a patient’s risk of thrombosis

Question 2

THrombophilia

aquired risk factors

Answer 2

Advancing age
Prior Thrombosis
Immobilization
Major surgery
Malignancy
Estrogens
Antiphospholipid antibody syndrome
Myeloproliferative Disorders
Heparin-induced thrombocytopenia (HIT)
Prolonged air travel

Question 3

thrombophilia

Inherited RF

Answer 3

Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Factor V Leiden mutation
Prothrombin gene mutation

Question 4

thrombophilia

HIGH Risk Classification & Management

Answer 4

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

Question 5

thrombophilia

MODERATE Risk Classification & Management

Answer 5

Moderate Risk needs vigorous prophylaxis in high-risk settings
1 event with a known provocative stimulus
Asymptomatic

Question 6

Factor V Leiden Mutation thrombophilia

general

Answer 6

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

Question 7

Factor V Leiden Mutation thrombophilia

Dx

Answer 7

Laboratory testing
Factor V Leiden mutation analysis

Question 8

Factor V Leiden Mutation thrombophilia

Factor V Leiden

Answer 8

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

Question 9

Heterozygous Factor V Leiden

Clin man

Answer 9

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

Question 10

Homozygous Factor V Leiden

risk of VTE

Answer 10

Increased risk of VTE (about 25-50X greater than general population)

Question 11

Prothrombin G20210A Mutation

general

Answer 11

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

Question 12

Prothrombin G20210A Mutation

Risk of VTE

Answer 12

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

Question 13

Antithrombin III Deficiency

general

Answer 13

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 = ?

Question 14

antithrombin III thrombophilia

Dx testing

Answer 14

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

Question 15

Protein C Deficiency

General

Answer 15

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

Question 16

Protein C (PC) Deficiency

more general and Dx

Answer 16

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

Question 17

Protein S

general

Answer 17

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

Question 18

Question 19

Antiphospholipid Antibody Syndrome

general

Answer 19

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

Question 20

Antiphospholipid Antibody Syndrome

labs

Answer 20

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

Question 21

Antiphospholipid antibody Syndrome

Tx

Answer 21

Indefinite anticoagulation for patients with definitive APS and thrombosis
Risk of thrombosis is 50% at 2 years after discontinuation

Question 22

Question 23

Warfarin (coumadin)

Warfarin and other Vitamin K Antagonists

Answer 23

Inhibit the synthesis of vitamin K-dependent clotting factors, which include:
Factors II, VII, IX, and X
(1972)
Anticoagulant proteins C and S

Question 24

Warfarin (Coumadin)

contraindications

Answer 24

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

Question 25

warfarin

Diagnosing hypercoagulable states in patients receiving warfarin

Answer 25

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

Question 26

Recognize that many dietary items and drugs can interact with vitamin K antagonists

Answer 26

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

Question 27

Warfarin Reversal

Answer 27

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

Question 28

Infusion/Injection Anticoagulants

Answer 28

Unfractionated heparin infusion/injection
Low molecular weight heparin injections
Fondaparinux injections

Question 29

Unfractionated Heparin

general

Answer 29

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

Question 30

A note about Heparin

Answer 30

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

Question 31

LMWH

general

Answer 31

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

Question 32

Fondaparinux (Arixtra)

general

Answer 32

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

Question 33

Direct Thrombin Inhibitor

Argatroban

Answer 33

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

Question 34

Dabigatran (Pradaxa)

use, contraindications, adverse effects

Answer 34

Use: VTE, Afib
Dosing (VTE): 150 mg twice daily
Avoid in moderate to severe renal impairment
Adverse effects: Hemorrhage, abdominal pain, dyspepsia

Question 35

Direct Oral Anticoagulants

Factor Xa inhibitors

Answer 35

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.

Question 36

Factor Xa Inhibitors more

Answer 36

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.

Question 37

Savaysa (Edoxaban)

Answer 37

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

Question 38

ELIQUIS (Apixaban)

Answer 38

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

Question 39

Xarelto (Rivaroxaban)

Answer 39

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

Question 40

Question 41

Thrombolytic Therapy

general

Answer 41

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%

Question 42

Contraindications to Thrombolysis

Answer 42

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

Question 43

Types of Thrombolysis

Answer 43

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

Question 44

Hirudotherapy

Answer 44

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