Hypercoagulable states & coagulopathy
Do not send thrombophilia labs during acute VTE or on anticoagulation (APS and prothrombin gene are selective exceptions).
When to send a thrombophilia panel
Do not test at the time of the event or during anticoagulant therapy (; ). If you test at all, wait >2 weeks after stopping anticoagulation. The panel is factor V Leiden, prothrombin gene mutation, protein C/S, antithrombin, and antiphospholipid antibodies.
Exceptions: you may start APS testing in the acute setting when the history is compelling (it changes the anticoagulant). The prothrombin gene mutation can also be sent on therapy.
Usually do not test
- Unprovoked VTE — it already warrants a conversation about indefinite anticoagulation
- VTE provoked by surgery
- VTE provoked by a clear medical syndrome (nephrotic syndrome, MPN, HIT)
- Women considering OCP/HRT with no family history of thrombophilia
- High-risk cancer (Khorana) — that is a prophylaxis decision, not a gene panel
Test on purpose
- VTE after a major nonsurgical transient risk (admission for pneumonia) or OCP/peri-pregnancy — controversial, but on the table
- Cerebral or splanchnic VTE — add JAK2 and, for hepatic/portal vein thrombosis, PNH
- Age <45, or a first-degree relative with VTE <45
- Recurrent or multiple thromboses; arterial thrombosis (APS)
- Warfarin-induced skin necrosis (protein C)
- Women considering OCP/HRT or pregnancy with a family history of high-risk thrombophilia; selected low/intermediate-risk cancer with a family history of VTE
Inherited hypercoagulable states
| Condition | Clinical pearl | How to test — and what falsely moves it |
|---|---|---|
| Factor V Leiden | Most common inherited hypercoagulable state | APC resistance assay (heparin interference is assay-dependent) → reflex FVL genetic test |
| Prothrombin gene (G20210A) | Second most common; ↑ prothrombin (FII) | PCR. Can be sent on anticoagulation |
| Protein C / S deficiency | Activated C/S inactivate FVa and FVIIIa. Associated with warfarin-induced skin necrosis — screen if there is a history | Free functional assays. Levels ↓ with acute thrombosis, VKA, liver disease, DIC, chemo, uremia (protein C), pregnancy/OCP/nephrotic syndrome (protein S). DOACs can ↑ measured protein C/S; HLD and nephrotic syndrome also interfere |
| Antithrombin III deficiency | More often inherited; acquired after L-asparaginase. Heparin works through ATIII — deficiency causes heparin resistance and higher dose requirements | Functional assay of FXa inhibition. Levels ↓ with acute thrombosis, UFH/LMWH, liver disease, nephrotic syndrome. Direct thrombin inhibitors and DOACs can ↑ measured ATIII |
APS and other acquired states
Antiphospholipid syndrome is primary or secondary to SLE and other autoimmune disease. The picture is unexplained venous or arterial thrombosis (especially in the young), adverse pregnancy outcomes, livedo reticularis/racemosa, valve disease, and thrombocytopenia.
- Clinical: thrombosis or pregnancy morbidity, plus lab criteria twice, 12 weeks apart — lupus anticoagulant (RVVT), anti-cardiolipin, anti-β2 glycoprotein-1.
- LA is unreliable on anticoagulation (false positive) and during acute thrombosis (false negative). Anti-cardiolipin and anti-β2GP1 are not affected that way.
- aPL antibodies also appear in infection, rheumatic disease, malignancy, and with medications. False-positive VDRL is a classic footnote ().
- Treat with a vitamin K antagonist (warfarin). Avoid DOACs in triple-positive APS — they fail.
- HIT: >50% platelet fall 5–10 days after heparin. Stop heparin and start an alternative (fondaparinux, argatroban) while assays are pending — see the thrombocytopenia note.
- Other acquired hypercoagulable states: malignancy (pancreas, MPN), pregnancy, OCPs/HRT, nephrotic syndrome, obesity, IBD, RA, central lines.
The bleeding workup
Primary hemostasis is platelets and VWD — mucocutaneous bleeding, petechiae, menorrhagia. Secondary hemostasis is clotting-factor activity — deep tissue, joints, viscera, brain, and a prolonged PT or PTT ().
- Rule out artifact, anticoagulant use, and systemic disease (cirrhosis, DIC, antibiotics, malnutrition, renal disease, cancer).
- Vascular disorders still bleed with normal coags: HHT, scurvy, Ehlers–Danlos.
Corrects
Factor deficiency
1:1 mix with normal plasma brings the PT/PTT back. with factor-specific assays.
Does not
Inhibitor
No or partial correction. Drugs (heparin), acquired factor inhibitors (VIII, V >> IX, XI — autoimmune disease, malignancy), or a nonspecific inhibitor such as lupus anticoagulant.
If still unexplained: VWD panel, platelet-function testing, thrombin time, fibrinogen, factor XIII.
| Normal aPTT | Prolonged aPTT | |
|---|---|---|
| Normal PT | Platelet dysfunction, VWD, factor XIII deficiency | Intrinsic pathway: ↓ VIII, IX (hemophilia), XI (Ashkenazi). VWD. ↓ XII, prekallikrein, HMWK (no bleeding). Lupus anticoagulant (prothrombotic) |
| Prolonged PT | Extrinsic pathway: ↓ VII, warfarin, liver disease, vitamin K deficiency | Common pathway: liver disease, DIC, vitamin K deficiency, warfarin. Rarely a common-pathway deficiency or inhibitor |
Hemophilia and DIC
Hemophilia is the most common severe bleeding disorder, X-linked: factor VIII (A) or IX (B). Clots form poorly and do not hold. Recurrent hemarthroses are the morbidity.
- Diagnosis: ↑ PTT (can be normal in mild disease) → 1:1 mix that corrects → factor-specific assay to separate A from B.
- Treatment: factor VIII or IX concentrates for prophylaxis or on-demand bleeding.
- Emicizumab is a bispecific antibody that mimics factor VIII, approved for prophylaxis in hemophilia A. Pipeline: fitusiran, concizumab, marstacimab, gene therapy.
DIC is massive activation of coagulation from sepsis, cancer, obstetric catastrophe, trauma, or pancreatitis. Factors are consumed: bleeding, microvascular thrombosis, MAHA, and organ failure (kidney, lung, CNS, adrenal). Phenotypes run thrombotic or hemorrhagic.
DIC
- ↑ PT/PTT, ↑ D-dimer, ↓ fibrinogen, ↓ platelets, schistocytes, ↑ LDH, ↓ haptoglobin
- Chronic DIC can have near-normal coags
- Factor VIII is low — it is made by endothelium, not hepatocytes
- Use a DIC score; treat the cause
Liver disease
- Also ↑ PT/PTT and can ↓ fibrinogen
- Factor VIII is normal or high
- INR does not predict bleeding the way it does on warfarin
- Do not 'correct' a 1.8 INR with FFP before a paracentesis as a reflex