Lecture 3 - Thrombophilia

blood clots that can block vessels

condition that increases the risk of forming clots

- Chronic or acute inflammation
- Uncontrolled platelet activation
- Blood coagulation control protein deficiencies
- Uncontrolled suppression of fibrinolysis

dangerous conditions like DVT (deep vein thrombosis), PE (pulmonary embolism), or artery blockages

Age
Diet
Immobilization
Lipid metabolism disorders
Pregnancy
Femoral or tibial fracture
Surgeries (hip, ..)
Smoking

A: It activates platelets and increases plasma viscosity, making blood more likely to clot.

A: It reduces the production of coagulation regulatory proteins, which can lead to abnormal clotting.

A: Acute Promyelocytic Leukemia (APL), which increases the risk of Disseminated Intravascular Coagulation (DIC).

A: It causes platelet activation, which can lead to blood clots.

A: Diabetes, cancer, infection, and autoimmune diseases.

A: It’s an autoimmune disorder where antibodies trigger increased clotting, raising the risk of thrombosis.

- AT deficiency
- Protein C deficiency
- (free) protein S deficiency
- APC resistance [FV Leiden (R506Q): GOF mutation in FV gene], has highest rate of thrombotic events (20-25%)
- Prothrombin G20210A: mutation causes FII elevation
- Hyperfibrinogenemia

A: It reduces the body's ability to stop clotting, increasing the risk of thrombosis.

A: It causes less control over clotting, making blood clots more likely to form.

A: It works with Protein C to control clotting, so a deficiency raises clotting risk.

A: It’s a mutation in the Factor V gene that makes it hard for the body to stop clotting, leading to the highest rate of clotting events (20–25%).

A: It causes increased production of Factor II (prothrombin), leading to a higher clot risk.

A: It’s a condition with high levels of fibrinogen, which makes clotting more likely.

A: No, clot formation depends on genetics, disease, and lifestyle factors.

APC resistance
 FV Leiden mutation
 Prothrombin mutation G20210A
 LAC profile
 AT activity
 PC activity
 PS activity
 Fibrinogen

A: It checks how well your body responds to Activated Protein C; a normal ratio is >1.8.

A: Wild type (meaning no mutation is present).

A: It’s a genetic mutation that increases clot risk; normal result is wild type (no mutation).

A: It checks for Lupus Anticoagulant; normal is negative.

A: 78%–126%.

A: 70%–140%.

A: 65%–140%.

A: 220–498 mg/dL.

"these are immune system proteins (antibodies) that accidentally attack your own body, especially the parts involved in blood clotting." - chat
A: APLAs (anti-phospholipid antibodies) are immunoglobulins (IgG or IgM) that bind to protein-phospholipid complexes and act as non-specific inhibitors.

A:
- Lupus anticoagulants (LACs),
- anticardiolipins (ACLs),
- anti-β2 glycoprotein I (anti-β2-GPI).

A: Antiphospholipid syndrome (APS), which increases the risk of clots and pregnancy complications.

Clinical correlation:
General population: 1–2%
5–15% of patients with thrombosis, mostly transient following infections (alloimmune)
or arise as autoimmune Abs in , and in 50% of patients with lupus (SLE).

A: Perform a Thrombin Time (TT) test to rule out heparin or dabigatran interference.

A: Heparin or thrombin inhibitor is unlikely—proceed with mixing study.
MIXING STUDY: Mix test plasma 1:1 with NP PTT on mixture.

A: Possible presence of heparin or dabigatran.

A: Add Hepzyme® to neutralize heparin and repeat the PTT.

A: Heparin was the cause; confirm with heparin assay.

A: Discontinue dabigatran and retest later.

A: Suggests a factor deficiency—confirm with factor assays.

A: Suggests the presence of an inhibitor, likely lupus anticoagulant (LAC).

A: Suspect a specific factor inhibitor or LAC; perform an assay for each.

A: Suggests a time-dependent factor deficiency.

-DTT - Dilute Thromboplastin Time → A sensitive test for LAC (Uses tissue factor and measures activation through Factor VIIa)
-DRVVT - Dilute Russell Viper Venom Test → Directly activates Factor X
- LAC-sensitive partial thromboplastin time (PTT) -> monitors intrinsic and common pathways

A: PTT (Partial Thromboplastin Time)

A: DRVVT tests for lupus anticoagulant by directly activating Factor Xa and measuring the common pathway.

A: It evaluates the extrinsic pathway and is sensitive to LAC interference.

A: It prolongs clotting times by interfering with phospholipid-dependent steps in the coagulation cascade.

4 step procedure

A: Perform a phospholipid-dependent clotting test such as a low-phospholipid PTT or DRVVT, known as the PTT or DRVVT screen.

A: It suggests the presence of an inhibitor like LAC rather than a clotting factor deficiency.

A: The clotting time shortens or corrects when excess phospholipids are added, using a test like PTT or DRVVT confirm.

A: Rule out other coagulation disorders (coagulopathies).

FV R506Q mutation aka FV Leiden

A: Factor V resists hydrolysis (breakdown) by activated protein C (APC).

A: It causes a 3-fold increase in thrombosis risk, or up to 18-fold in homozygous individuals.

A: A clot-based APC ratio assay and a molecular FV mutation test (to check for zygosity).

A: A normal APC ratio is >1.8. A ratio ≤1.8 implies APC resistance and must be confirmed with molecular testing.

A: If adding APC doesn’t significantly prolong the clotting time (PTT), it suggests APC resistance.

A: A guanine (G) to adenine (A) mutation at the 3' untranslated region (3'UTR) of the prothrombin gene.

A: It increases prothrombin levels and raises thrombosis risk by 2–3 times in heterozygotes.

A: 0.3–2.4% in the general population and 5–18% in familial thrombosis cases.

A: By using molecular genetic assays.

A: Antithrombin inhibits thrombin, Xa (10), IXa (9), XIa. (11), and XIIa (12) to prevent excessive clotting.

A: AT activity is less than 70% of normal.

A: Liver disease, nephrotic syndrome, prolonged heparin therapy, contraceptives, and DIC.

A: More than 90% are quantitative, meaning low AT antigen levels.

A: Activity less than 65% of normal.

A: 1.6 to 11.5 times higher risk of DVT and PE.

A: Neonatal purpura fulminans, which is deadly if untreated.

When levels are falsely decreased due to:

Within 14 days of acute inflammation

After stopping Coumadin therapy

During pregnancy

In DIC, liver or kidney disease, vitamin K deficiency, or oral contraceptive use.

A: It is triggered by a systemic disease and causes generalized, uncontrolled activation of the hemostasis system.

A: Hemorrhage (bleeding) is the major issue.

A: Consumptive coagulopathy or defibrination syndrome.

A:
Abnormal pattern on PBS and CBC
Thrombocytopenia
Prolonged PT, PTT, and TT
Low fibrinogen
Increased FDPs, especially D-dimer

A: It can be fatal in 50% of cases if not managed quickly and requires immediate testing and intervention.

A: Endothelium damage (e.g., trauma) releases TF, which activates clotting.

A: Bacterial infections or septicemia release endotoxins that over-activate clotting.

A: It exposes the endothelium, which activates clotting.

A: They damage vessels in conditions like HIT, AHTR, and graft rejection, leading to clotting.

A: They release proteolytic enzymes that activate the coagulation system.

A: They directly activate clotting pathways.

A: It disrupts normal enzyme function and can trigger abnormal clotting.

A: It causes excessive clotting, contributing to DIC.

TF release: ENDOTHELIUM DAMAGE, E.G. TRAUMA
Endotoxin: SEPTICEMIA, BACTERIAL INFECTION
Endothelium exposure during vasodilation: HEAT STROKE
Circulating immune complexes: HIT, AHTR, GRAFT REJECTION
Secretion of proteolytic enzymes: APL, AMML
Toxins: SNAKE VENOM
Acidosis: DIABETES MELLITUS
PLT activation: THROMBOCYTHEMIA, VASCULAR SURGERY

150,000-450,000/ uL; <150,000/ uL

11-14 sec;
>14 sec

25-35 sec; >35 sec

Prolonged;
Fibrinogen levels <80 mg/dL, elevated FDPs (Fibrin Degradation Products), and soluble fibrin monomer all prolong thrombin time and reptilase time.

0-240 ng/mL DDU or 0-500 ng/mL FEU;
>240 ng/mL DDU or >500 ng/mL FEU, often 10,000-20,000 ng/mL

220-498 mg/ dL;
<220 mg/dL, often higher, because fibrinogen is an acute phase reactant.

Platelet count
Peripheral blood film exam
PT
PTT
Thrombin time, reptilase time
D-dimer
Fibrinogen

-Protein C, Protein S, and AT activity assays
-Plasminogen, tissue plasminogen activator, plasminogen activator
inhibitor-1 (PAI-1)
-Soluble fibrin monomer
-Factor assays: II (prothrombin, V, VIII, X).

<50%; use to monitor plasma, AT concentrate

Decreased; may be useful for analyzing systemic fibrinolysis; specimen management protocol must be strictly observed

Positive; hemagglutination assay

<30%; Factors V and VIII rise in inflammation; assays may give misleading results

A: An immune response against platelets after exposure to heparin (UFH or LMWH), leading to thrombocytopenia

A: Risk of thrombosis (blood clots), which occurs in 0.5–5% of patients on UFH (less with LMWH).

A: DVT, PE, MI, stroke, limb ischemia, and skin lesions at injection sites.

A: Mortality is 30%, and 20% of survivors may require amputation.

A: Diagnosis and treatment are complex due to the immune-mediated nature and need for specific testing and management.

A: An IgG antibody targets the PF4-heparin complex (requires heparin to be present).

A: FcγRIIa (CD32) receptor on platelets.

A: Platelet clearance, microparticle release (which promotes clotting), and thrombocytopenia.

A: It triggers inflammation involving monocytes, PMNs, and macrophages.

A: Platelet activation, thrombosis (clotting), and inflammation.

A: Every 48 hours during and after heparin therapy.

A: A 30–50% decrease in platelet count after heparin treatment compared to before.

A: Often below 150,000/ uL, but bleeding is rare in HIT patients.

A: 5–10 days after starting heparin.

A: Platelet count may drop rapidly, within hours.

A: Up to 30 days after stopping heparin therapy.

A: Thrombosis in 30% of heparin-treated patients with thrombocytopenia. Even if no clot is seen, monitor for 30 days after platelet drop.

A: To help those at risk of serious cardiovascular events caused by blood clots.

A: By preventing the enlargement of existing thrombi and formation of new ones.

A: They help keep the thrombus localized.

A: They help the body’s thrombolytic system dissolve existing clots.

A: By causing a deficiency of active clotting factors.

A: A substance that inhibits clotting factors through an intermediate mechanism.

A: A substance that directly blocks clotting factors.

Can cause deficiency of active clotting factors
• Can be indirect inhibitors of factors
• Can be direct inhibitors of factors

A: Uncontrolled bleeding.

A: Nosebleeds, bruising, and bleeding after minor injuries.

A: Between 1% and 3%.

A: Dose, patient condition, and age.

A: A reversal mechanism.

Coumadin/Warfarin
Heparin
Direct Oral Anticoagulants or DOACs

A: It blocks vitamin K, which is needed to make clotting factors.

A: It indirectly inhibits clotting by activating antithrombin (AT), which blocks thrombin, IXa (9), Xa (10), XIa (11), and XIIa (12).

Xa inhibitor

A: Thrombin (it is a Direct Thrombin Inhibitor or DTI).

A: Factor Xa.

in ER
during surgery
post-surgery
'bridging' to Coumadin or DOACs
Effect is immediate

A: Heparin and Coumadin (Warfarin).

A: PT/INR, PTT, and FXa assay.

A: Standard doses are effective and have little variability between patients.

A: Yes, they can interfere with lab tests even though they don't require routine monitoring.

A: To check if they are present in the body, such as before surgery or during emergencies.

DOAC

Warfarin - generic name but coumadin is mostly used; one of the 20 most prescribed drugs in North America

it blocks the activity of vit K epoxide reductase required for gamma-carboxylation of vita K-dependent coag factors (SCZ27910)

prevent stroke and heart attacks, post-surgery/trauma VTE and recurrence of DVTs & PE

-from moldy sweet clover- discovered when cows died after eating moldy clover in fields.
-Also used as rat poison in very different dose and form

around 5 days (bridging with UFH, LMWH or Fondaparinux)

with INR ;
INR of 2-3
Cardiac valves 2.5-3.5

24 hrs ;
-checked every 2-4 days until INR consistent (2-3 times a week)
-checked very 4 weeks when stabilized until discontinued
some patients on long-term therapy

diet high in Vitamin K!

non-urgent and urgent

This is when there's no bleeding or surgery, just a high INR (meaning too much anticoagulation).

Stop taking Coumadin
Take oral or injection of Vitamin K

A: Stop Coumadin, give IV Vitamin K, and give a blood product that provides clotting factors.

A: Prothrombin Complex Concentrate (PCC).

A: DVT, PE, and myocardial infarction.

A: Unfractionated heparin (UFH) and low molecular weight heparin (LMWH).

A: It activates antithrombin to block clotting enzymes (serine proteases), except Factor VIIa. (7)

A: LMWH cannot inhibit thrombin but efficiently inhibits Factor Xa. (10)

A: It can be given in fixed doses, works as well as UFH, is easier to use, and usually doesn’t require lab monitoring.