Coagulation Lecture 3: Thrombophilia REDUCED

• Age

• Diet

• Immobilization

• Lipid metabolism disorders

• Pregnancy

• Femoral/tibial fracture

• Surgery

• Smoking

Risk factors for thrombosis (8)

• MPN (PLT activation, plasma viscosity)

• Liver disease (low coag reg proteins)

• Leukemia (APL, DIC)

• PNH (PLT activation)

• Chronic inflammation

• Anti-phospholipid syndrome

Risk factors for thrombosis associated with systemic diseases (6)

• AT deficiency

• Protein C deficiency

• Protein S (free) deficiency

• APC resistance (FV Leiden R506Q)**

• Prothrombin G20210A (FII elevation)

• Hyperfibrinogenemia

Congenital risk factors for thrombosis (6)

ratio > 1.8

Normal APC resistance ratio

78-126%

AT activity reference interval

70-140%

PC activity reference interval

65-140%

PS activity reference interval

220-498 mg/dL

Fibrinogen reference interval

Anti-phospholipid antibodies (APLAs)

Immunoglobulins (IgG or IgM) that binds protein-PL complexes, aka non-specific inhibitors

• lupus anticoagulants (LAC)

• anticardiolipins (ACLs)

• anti-β2-GPI

Three major types of anti-phospholipid antibodies

FV resists hydrolysis by APC

Mechanism of action for FV Leiden (FV R506Q) mutation

• 3x increase risk of thrombosis

• 18x risk in homozygous

Clinical significance of FV Leiden (FV R506Q) mutation (2)

• Clot-based assay

• FV mutation assay (also check zygosity)

Laboratory detection of FV Leiden (FV R506Q) mutation (2)

Guanine → adenine at 3’UTR

What is the mutation involved in prothrombin G20210A

2-3x

Prothrombin G20210A mutation increases the risk of thrombosis by…

Molecular genetic assay

Laboratory detection of prothrombin G20210A

<70%

Antithrombin (AT) deficiency is defined as AT activity (—%—) of normal

• Liver disease

• Nephrotic syndrome

• Prolonged heparin therapy

• Contraceptives

• DIC

Antithrombin (AT) deficiency can be acquired during… (5)

> 90%

Congenital antithrombin (AT) deficiency is (—%—) quantitative

< 65%

Protein C and S deficiency is defined as activity (—%—) of normal

1.6-11.5x

In protein C and S deficiency, there is a (——)-fold increase in thrombosis (DVT and PE) risk in heterozygotes

Neonatal purpura fulminans

Homozygous PC or PS deficiency results in… (deadly if left untreated)

Coumadin (coumadin-induced skin necrosis)

Challenges with (——) therapy in heterozygous PC deficiency

Disseminated intravascular coagulation (DIC)

Generalized and uncontrollable activation of the hemostasis system triggered by a systemic disease; consumptive coagulopathy or defibrination syndrome, it engages the whole hemostasis from vessels up to the fibrinolytic system

• Pattern on PBS and CBC

• Thrombocytopenia

• Prolonged PT/PTT/TT

• Low fibrinogen

• increased FDPs, especially D-dimer

Laboratory picture of DIC (5)

• TF release*

• Endotoxin

• Endothelium exposure during vasodilation (heat stroke)

• Circulating immune complexes (HIT, AHTR, graft reject)

• Secretion of proteolytic enzymes (APL, AMML)

• Toxins

• Acidosis

• PLT activation

DIC pathophysiology (8)

Heparin-induced thrombocytopenia

An immune response against PLTs following exposure to therapeutic heparin (UFH or LMWH) displayed as thrombocytopenia

0.5-5%

The big clinical concern of HIT is risk of thrombosis, (—%—) with UFH (less in LMWH)

• IgG

• Platelet factor 4-heparin

In HIT, an antibody (——) recognizes the (——) complex

• Fc

• Fc𝛄RIIa

In HIT, the (——) portion of IgG:H:PF4 complex binds (——) on PLTs, leading to PLT activation, PLT clearance, PLT microparticle formation (prothrombotic), thrombocytopenia

• PLT activation

• Thrombosis

• Inflammation (complex binds to ECs)

Main outcomes of HIT (3)

30-50%

HIT is considered when there is a (—%—) decrease in PLT count post-heparin vs. pre-treatment

48 h

When observing for HIT, PLT count is performed once every (——) during and after heparin therapy

5-10 days

In primary HIT, PLT count declines (——) after heparin initiation

< 120 days

In HIT, if a patient was heparinized (——) before, PLT fall occurs faster (within hours)

30 days

In delayed HIT, reaction may show up (——) after cessation of heparin therapy

Thrombosis in heparin-treated pt with thrombocytopenia

Strong signal for HIT

¹⁴C-serotonin release assay (SRA)

Reference test for HIT detection

• Prevent enlargement/development of thrombi

• Keep thrombi localized

• Augment natural thrombolytic system

Objectives of anti-coag drugs (3)

• Deficiency of active clotting factors

• Indirect inhibition of factors

• Direct inhibition of factors

Describe the different modes of action for anticoagulants (3)

Reversal mechanism

Due to bleeding risk, anticoagulants should have a (——)

• Indirect

• Activates: AT

• Inhibits: IXa, Xa, XIa, XIIa

Heparin characteristics (direct/indirect, activates, inhibits)

Fondaparinax

Heparin anticoagulant that is specific to Xa inhibition

• Dabigatran (DTI)

• Apixaban, Rivaroxaban, Edoxaban (FX inhibitors)

Examples of direct oral anticoagulants (DOAC) (4)

• Heparin

• Coumadin and DOAC

(——) is primarily used in the hospital in the ER, surgery, post-surgery, and bridging to other anticoagulants. Its anticoagulant effect is immediate. On the other hand, (—2—) are used for long-term use depending on the physician, comorbidities, and condition of the patient

• PT/INR

• PTT

• FXa assay

Laboratory tests that are commonly used to monitor heparin and coumadin therapy (3)

Warfarin

(——) is the generic name while Coumadin is the most common brand name; it is one of the 20 most prescribed drugs in North America

• vit K epoxide reductase

• SCZ27910

Coumadin functions by blocking the activity of (——) required for 𝛄-carboxylation of vitamin K-dependent coag factors (——)

• UFH

• LMWH

• Fondaparinax (Xa inhibitor)

With Coumadin therapy, existing factors are not affected (still functional), so the full effect of coumadin will take around 5 days when bridged with (—3—)

• Therapeutic: 2-3

• Cardiac valves: 2.5-3.5

Coumadin therapy can be monitored with INR, with the therapeutic range being determined by the physician. Typically, this range is (——), with the cardiac valves being (——)

• 24 hours

• 2-4 days

• 4 weeks

Coumadin therapy can be monitored with PT, which is conducted (——) after starting therapy. PT is then checked every (——) until INR becomes consistent. Once consistent,PT is checked every (——) until therapy is discontinued.

Vitamin K

Diets high in (——) reduces the effect of Coumadin; patients with coumadin therapy still must maintain a regular, balanced diet as changes in diet can change INR. This is one of the reasons why coumadin therapy is monitored regularly

(Just to reduce INR)

• Stop taking Coumadin

• Take oral/injection vitamin K

Steps to reverse coumadin in a non-urgent setting (2)

(Bleeding or emergency surgery)

• Stop taking coumadin

• IV vitamin K

• Give blood product with usable factors

Steps to reverse coumadin in an urgent setting (3)

• Prothrombin complex concentrate

• Plasma (if PCC not available)

Blood products with usable factors (2)

serine proteases (except VIIa)

UFH activates AT to inhibit (——)

LMWH

derived from UFH by enzymatic depolymerization; has reduced inhibitory ability against thrombin vs FXa

LMWH

can be administered in fixed doses (have predictable pharmacokinetics) and without the need for dose adjustment based on laboratory monitoring