DVT Analysis — Bill Paseman

1 — Clinical Timeline

2013-11-27

First DVT — Left Leg

No anticoagulation at time of event. Initial treatment: warfarin.

2014-02

Second DVT — Warfarin Failure

Recurrence despite therapeutic warfarin. IVC filter placed. Switched to heparin → Lovenox.

2014-04-22

IVC Filter Removed

Transitioned to aspirin 81mg daily. Consultants recommended Xarelto or Eliquis at this time — recommendation not implemented.

2022-02

Chronic DVT Confirmed by Ultrasound

Still on aspirin 81mg. Evidence of residual/chronic thrombosis.

2025-02

Third DVT — Aspirin Failure

New DVT event on aspirin 81mg. Second anticoagulation regimen failure. Indefinite DOAC anticoagulation now strongly indicated.

Event	Anticoagulation at Time	Outcome
First DVT (2013-11)	None	DVT developed
Second DVT (2014-02)	Warfarin	Warfarin failure
Chronic DVT (2022-02)	Aspirin 81mg	Ongoing thrombosis
Third DVT (2025-02)	Aspirin 81mg	Aspirin failure — second regimen failure

2 — Germline Genomic Findings (WBA WGS, 90x, hg19)

Classic Thrombophilia Panel — Results from Your Data

Key Negative Findings

The two most common hereditary thrombophilias — Factor V Leiden and Prothrombin G20210A — are both definitively absent from your germline WGS data. This shifts the explanation toward your compound multi-factorial risk profile.

Gene	Variant	Status	Population VTE Risk	Finding
F5	p.Arg534Gln / rs6025 Factor V Leiden	ABSENT	3–80× VTE	Homozygous wild-type confirmed at chr1:169519049. FVL definitively excluded.
F2	G20210A / rs1799963 Prothrombin mutation	ABSENT	2–3× VTE	No variant at chr11:46761055 (3' UTR). Prothrombin G20210A definitively excluded.
PROC	Protein C deficiency	CODING CLEAN	5–10× VTE	Only synonymous variants in coding region. Functional activity assay still required — coding clean ≠ normal activity.
PROS1	Protein S deficiency	CODING CLEAN	5–10× VTE	Only synonymous variants. Functional assay required.
SERPINC1	Antithrombin III deficiency	CODING CLEAN	10–20× VTE	Very few variants in gene region; none in coding annotation. Functional assay required — antithrombin deficiency is most often detected by activity, not sequencing.

Coagulation Gene Variants Found in Your Germline Data

Gene	Variant	Zygosity	Pop. Freq.	Predictors	Assessment
VWF	p.Gly2705Arg `rs7962217`	Heterozygous	4.5%	SIFT: Damaging PolyPhen: Prob. Damaging MutAssessor: Medium	POTENTIALLY SIGNIFICANT — Rare-ish variant in von Willebrand Factor with convergent damaging predictions. VWF dysfunction can impair platelet adhesion and affect fibrinolysis. VWF activity + antigen levels should be checked clinically.
MTHFR	p.Ala222Val / C677T `rs1801133`	Homozygous	24.5%	SIFT: Damaging Labcorp confirmed 2022	CONFIRMED FUNCTIONAL — Decreased enzyme activity → impaired homocysteine remethylation → elevated homocysteine (your labs: 10.9–15.0 mcmol/L). Homocysteine causes direct endothelial injury and impairs protein C activation.
F12	p.Ala207Pro `rs17876030`	Homozygous	94%	SIFT: Tolerated PolyPhen: Benign	Very common variant. Factor XII (contact pathway) — complex role in both coagulation and fibrinolysis. Likely benign at this frequency.
F13A1	p.Val35Leu `rs5985`	Heterozygous	15%	SIFT: Tolerated PolyPhen: Benign	Factor XIII V34L — mixed literature on thrombosis risk; affects clot crosslinking rate. Likely not a primary driver.
F2	p.Thr165Met `rs5896`	Heterozygous	22%	SIFT: Damaging PolyPhen: Benign	Common coding variant in prothrombin. PolyPhen benign overrides SIFT here. NOT the pathogenic G20210A 3' UTR mutation.
KLKB1	p.Ser143Asn `rs3733402`	Heterozygous	60%	SIFT: Tolerated PolyPhen: Benign	Plasma prekallikrein — very common variant; likely benign.

Genes Requiring Additional Assessment

Gene	Variant of Interest	Why Not in Current Data	Clinical Importance
SERPINE1 (PAI-1)	4G/5G promoter indel `rs1799768`	Promoter indel — not captured in coding SNP annotation file	HIGH — 4G/4G homozygous = elevated PAI-1 = impaired fibrinolysis = increased VTE risk. Needs indel file analysis or clinical PAI-1 activity test.
PROC / PROS1 / SERPINC1	Functional deficiency	Coding regions appear clean — but functional deficiency occurs without coding mutations	HIGH — Cannot exclude deficiency by sequencing alone. Activity assays required.
Antiphospholipid antibodies	Lupus anticoagulant, aCL, anti-β2GPI	Acquired immune phenomenon — not detectable by WGS	URGENT — Antiphospholipid syndrome (APS) is a common cause of recurrent DVT, is acquired not inherited, and requires specific antibody testing. Most important diagnosis to exclude.

3 — Non-Genetic Prothrombotic Risk Profile

These lab and clinical findings are as important as, or more important than, the genetic findings in explaining your recurrent DVT. Each represents a modifiable target.

Lp(a)

106 mg/dL (ref <30)

D-dimer

0.84–1.07 (ref <0.6)

CRP (cardiac)

3.96–5.81 (ref <3.0)

Homocysteine

10.9–15.0 (target <10)

Uric acid

8.7 mg/dL (ref <6.0)

HbA1c

5.9% (ref <5.7%)

IL-6

2.8–7.9 pg/mL

Free T3

2.8–2.9 (ref 4.4, LOW)

Risk Factor	Your Value	Threshold	Thrombosis Mechanism
Lp(a)	106 mg/dL	<30 mg/dL	Structural homology to plasminogen — competitively inhibits fibrinolysis; deposits in vessel walls promoting atherothrombosis
Homocysteine	10.9–15.0 mcmol/L	<10 optimal	Direct endothelial injury; impairs protein C activation; promotes oxidative stress on vascular endothelium
MTHFR C677T	Homozygous	—	Mechanism for hyperhomocysteinemia: impaired remethylation of homocysteine to methionine. Cannot efficiently process folic acid.
D-dimer (baseline)	0.84–1.07 mcg/mL	<0.6	Elevated at baseline = coagulation system is already "running hot" — active fibrin formation and breakdown at rest
CRP (cardiac)	3.96–5.81 mg/L	<3.0	Inflammatory activation of coagulation cascade; CRP directly upregulates tissue factor on monocytes
IL-6	2.8–7.9 pg/mL	<13 ref	Stimulates hepatic acute phase response; increases fibrinogen and Factor VIII; promotes platelet activation
Uric acid	8.7 mg/dL	<6.0 mg/dL	Endothelial dysfunction; vascular inflammation; gout flares create acute systemic inflammatory activation of coagulation
HbA1c (prediabetes)	5.9%	<5.7%	Insulin resistance increases PAI-1 (impairs fibrinolysis), fibrinogen, and platelet hyperreactivity
Free T3 (low)	2.8–2.9 pg/mL	4.4 reference	Low T3 state reduces fibrinolytic activity, decreases endothelial function, and impairs homocysteine clearance
OSA (very severe)	Active	—	Repeated nocturnal hypoxemia activates coagulation cascade; elevates fibrinogen and Factor VIII; impairs fibrinolysis; increases platelet activation
Bradycardia	HR <60 BPM	—	Reduced venous return velocity — contributes to venous stasis component of Virchow's triad

4 — Virchow's Triad: All Three Arms Active

Virchow's triad describes the three categories of factors that cause thrombosis. This patient has active contributors in all three arms simultaneously.

Hypercoagulability

MTHFR C677T homozygous → ↑ homocysteine
Lp(a) 106 mg/dL → inhibits fibrinolysis
Elevated fibrinogen (IL-6 driven)
Elevated Factor VIII (OSA + inflammation)
Prediabetic PAI-1 elevation
Possible Protein C/S/AT deficiency (untested)
Possible APS (not yet excluded)

Endothelial Injury

Homocysteine (direct toxic endothelial effect)
Lp(a) (vascular wall deposition)
Uric acid (endothelial dysfunction)
OSA hypoxia (repeated ischemia-reperfusion)
Chronic inflammation (CRP, IL-6)
VWF p.Gly2705Arg (possible platelet adhesion defect)

Venous Stasis

Bradycardia (HR <60 BPM) → reduced venous return
Prior DVT → residual venous damage / impaired valve function
Chronic DVT (2022) → established stasis
OSA → nocturnal reduced mobility and altered hemodynamics

5 — Most Likely Explanation for Three DVTs

Conclusion

Multi-factorial compound prothrombotic state — not a single hereditary defect. The classic hereditary thrombophilias (Factor V Leiden, Prothrombin G20210A) are absent. The risk derives from the accumulation of multiple moderate-risk factors that together create a substantially elevated baseline thrombotic risk, combined with two specific high-impact factors: Lp(a) 106 mg/dL and severe OSA, both of which are under-recognized as major VTE contributors.

    MTHFR C677T homozygous

       → Elevated homocysteine (10.9–15.0 mcmol/L)

       → Direct endothelial injury + impaired protein C activation

    Lp(a) 106 mg/dL

       → Inhibits fibrinolysis (plasminogen competition)

       → Endothelial lipid deposition

    Severe OSA (very severe)

       → Repeated nocturnal hypoxemia → coagulation activation

       → Elevated Factor VIII + fibrinogen + platelet hyperactivity

    Low Free T3 (2.8–2.9 vs ref 4.4)

       → Reduced fibrinolytic activity

       → Worsens homocysteine clearance

    Chronic inflammation (CRP, IL-6 elevated)

       → Upregulates tissue factor + fibrinogen

       → Activates platelets

    Elevated D-dimer at baseline (0.84–1.07)

       → Coagulation system already activated at rest

    VWF p.Gly2705Arg (het, 4.5% freq, damaging)

       → Possible VWF dysfunction — clinical testing needed

    PAI-1 4G/5G status — not yet assessed

       → If 4G/4G: further impairs fibrinolysis — clinical testing needed

    Antiphospholipid syndrome — NOT YET EXCLUDED

       → Acquired autoimmune prothrombotic state — requires antibody testing

6 — Recommended Clinical Workup

Timing Note for Thrombophilia Testing

Protein C, Protein S, and Antithrombin III activity levels are falsely low during acute DVT and while on anticoagulation. These should ideally be checked at least 3 months after the acute event, off anticoagulation (or with appropriate test interpretation caveats). Antiphospholipid antibodies require two positive tests at least 12 weeks apart for diagnosis.

A. Antiphospholipid Syndrome (APS) — Highest Priority

Test	Why	Priority
Lupus anticoagulant	Most sensitive APS test; causes paradoxical prolongation of aPTT	Urgent
Anticardiolipin IgG + IgM	APS antibody — requires 2 positives 12 weeks apart	Urgent
Anti-β2 glycoprotein-1 IgG + IgM	Most specific APS antibody; triple-positive APS = highest thrombotic risk	Urgent

B. Functional Coagulation Testing

Test	Why	Priority
Protein C activity + antigen	Coding region clean but functional deficiency possible; 5–10× VTE risk if deficient	High
Protein S activity + free/total antigen	Coding region clean; functional assay required	High
Antithrombin III activity + antigen	Highest VTE risk of the three (10–20×); coding clean but activity assay required	High
Factor VIII activity	Elevated FVIII (>150%) is an independent VTE risk factor; common and under-tested; raised by OSA and chronic inflammation	High
VWF activity (ristocetin cofactor) + antigen	Functionally assess the VWF p.Gly2705Arg damaging variant found in WGS	Medium
PAI-1 activity (or 4G/5G genotype)	Elevated PAI-1 impairs fibrinolysis; common in prediabetes/insulin resistance; 4G/4G genotype → increased expression	Medium
Fibrinogen level	Hyperfibrinogenemia (driven by IL-6) increases clot burden	Medium

C. Labs to Recheck

Test	Current Value	Target	Why Recheck
Homocysteine	10.9–15.0 mcmol/L (last 2022)	<10 mcmol/L	Track response to supplementation; confirm L-methylfolate switch is effective
Free T3 + TSH + T4	Free T3 2.8–2.9 (last 2022)	T3 4.4+ pg/mL	Low T3 worsens coagulation — reassess for treatment
D-dimer	0.84–1.07 mcg/mL baseline	<0.6	Track response to anticoagulation; baseline hypercoagulability marker
CRP + IL-6	CRP 3.96–5.81, IL-6 2.8–7.9	CRP <3.0	Track inflammation reduction with interventions

7 — Treatment Recommendations

Initiate Therapeutic DOAC — Immediately

Apixaban (Eliquis) 10mg BID × 7 days, then 5mg BID; OR rivaroxaban (Xarelto) 15mg BID × 21 days, then 20mg daily. Your consultants recommended this since 2014. The third DVT makes it urgent. Duration: indefinite — two unprovoked recurrences = strong guideline recommendation for lifelong anticoagulation.

Exception: If APS (triple-positive) confirmed → warfarin INR 2–3 may be preferred over DOACs per current guidelines (RAPS trial, ASTRO-APS).

Fix Homocysteine / MTHFR — Active Target

Switch from standard folic acid to L-methylfolate (5-MTHF, e.g., Deplin 15mg or equivalent) + methylcobalamin B12 (not cyanocobalamin). MTHFR C677T homozygous cannot efficiently convert folic acid to the active form — the bypass is essential. Target homocysteine <10 mcmol/L. Check homocysteine 8 weeks after switch.

Meta-analyses support homocysteine lowering reducing VTE recurrence risk.

Treat Lp(a) — High-Impact Target

At 106 mg/dL, Lp(a) is substantially elevated and contributing to both fibrinolysis inhibition and endothelial damage.

PCSK9 inhibitor (evolocumab/Repatha or alirocumab/Praluent) — reduces Lp(a) 25–30% AND LDL.
Olpasiran (FDA-approved 2024) — reduces Lp(a) >90% specifically; discuss with cardiologist.
Niacin — reduces Lp(a) ~30%; limited by side effect profile.

Maximize OSA Treatment

Severe untreated or poorly controlled OSA directly activates coagulation via hypoxic episodes: elevates Factor VIII, fibrinogen, and platelet reactivity. Ensure optimal CPAP adherence (AHI <5 on therapy). Consider evaluation for ASV or BiPAP if CPAP is not achieving adequate control.

OSA control has been shown to reduce thrombotic risk and improve homocysteine clearance.

Reduce Uric Acid + Inflammation

Xanthine oxidase inhibitor: allopurinol 100–300mg or febuxostat 40–80mg. Target uric acid <6.0 mg/dL. Reduces vascular inflammation and endothelial dysfunction.

Statin: independently reduces VTE recurrence ~50% (JUPITER trial) via anti-inflammatory pleiotropic effects on coagulation, independent of LDL effect.

Colchicine 0.5mg daily — emerging data (COLCOT, LoDoCo2) for vascular event reduction via NLRP3 inflammasome inhibition.

Address Low Free T3 + Prediabetes

Low T3: endocrinology consultation for thyroid optimization — consistently low Free T3 (2.8–2.9 vs ref 4.4) despite normal TSH warrants evaluation for T3 supplementation or underlying thyroid dysfunction.

Prediabetes (HbA1c 5.9%): dietary intervention; consider metformin (also reduces PAI-1 expression and platelet reactivity). Reversing insulin resistance reduces PAI-1, fibrinogen, and platelet hyperactivity — all contributing to thrombotic risk.

If APS Is Confirmed

APS-Specific Treatment Note

If antiphospholipid syndrome is confirmed (particularly triple-positive: lupus anticoagulant + aCL + anti-β2GPI), current guidelines (2023 ACR/EULAR) recommend warfarin with target INR 2–3 rather than DOACs for venous APS, based on the RAPS and ASTRO-APS trials showing higher recurrence rates with rivaroxaban in APS. This would change the anticoagulation strategy significantly.

8 — Genomic Summary: What the Data Tells Us vs. Doesn't

Question	Answer	Source
Factor V Leiden present?	ABSENT — definitively excluded	WBA germline WGS
Prothrombin G20210A present?	ABSENT — definitively excluded	WBA germline WGS
Protein C gene variants?	Coding clean — functional assay still needed	WBA germline WGS
Protein S gene variants?	Coding clean — functional assay still needed	WBA germline WGS
Antithrombin III gene variants?	Coding clean — functional assay still needed	WBA germline WGS
MTHFR C677T?	HOMOZYGOUS — confirmed functional	WBA germline WGS + Labcorp 2022
VWF abnormality?	Potentially — damaging rare variant (p.Gly2705Arg); needs functional testing	WBA germline WGS
PAI-1 4G/5G status?	Not yet assessed — needs indel analysis or clinical lab	Indel file or clinical lab
Antiphospholipid syndrome?	Cannot be assessed by WGS — requires clinical antibody testing (URGENT)	Clinical lab — order now
Protein C/S/antithrombin functional deficiency?	Cannot be excluded by WGS — activity assays required	Clinical lab
Lp(a) elevation contributing?	YES — 106 mg/dL (ref <30) inhibits fibrinolysis	Labcorp 2022
OSA contributing?	YES — very severe; directly activates coagulation cascade	Clinical diagnosis 2017
Hyperhomocysteinemia contributing?	YES — 10.9–15.0 mcmol/L; MTHFR mechanism confirmed	Serial labs 2022

Overall Assessment

The most common hereditary thrombophilias are absent. The thrombotic risk profile is driven by a compound multi-factorial picture: hyperhomocysteinemia (MTHFR C677T homozygous), Lp(a) 106 mg/dL, severe OSA, chronic inflammation, prediabetes, low Free T3, and elevated baseline D-dimer. All of these are modifiable targets. The most urgent unresolved question is antiphospholipid syndrome, which must be excluded by antibody testing and would change the anticoagulation strategy. Indefinite therapeutic DOAC anticoagulation is indicated now regardless of further workup results.