Protein C deficiency is even more common than antithrombin deficiency (0.02–0.2%) but less common than Protein S deficiency (~0.9%) as an inherited thrombophilia. ^[1]

• Data on the exact prevalence of Protein C deficiency in the Hong Kong Chinese population is limited, but inherited thrombophilia overall is less common in East Asian populations compared to Caucasians.
• Factor V Leiden and Prothrombin G20210A mutation — the two most common inherited thrombophilias in Caucasians — are extremely rare in Chinese/East Asian populations. This means that when a young Chinese patient presents with unprovoked VTE, the relative proportion attributable to Protein C, Protein S, and Antithrombin deficiencies is higher than in Caucasian cohorts.
• In Hong Kong, clinicians should also remember that Factor XII deficiency (found in ~20% of the local population) is a common cause of isolated prolonged APTT but does not cause bleeding or thrombosis — this is a red herring during thrombophilia workup. ^[3]

• Autosomal dominant inheritance → affects males and females equally (unlike haemophilia A/B which is X-linked).
• Heterozygous individuals typically present with their first VTE event between ages 10–50, with a median age of first thrombosis around 20–30 years.
• Homozygous individuals present in the neonatal period with purpura fulminans.

Antithrombin deficiency is the most clinically severe inherited thrombophilia. Protein C deficiency has an OR for thrombosis of approximately 7.5, intermediate between antithrombin deficiency (16.3) and protein S deficiency (5.4). ^[1]

Protein C is mainly synthesized in the liver. ^[1] This is critical because:

• Liver disease (cirrhosis, acute liver failure) → reduced Protein C levels (acquired deficiency)
• Vitamin K deficiency or warfarin therapy → impaired post-translational modification (γ-carboxylation) of Protein C → dysfunctional protein

Protein C is a vitamin K–dependent serine protease zymogen (i.e. it circulates in an inactive form until activated). Its gene is PROC, located on chromosome 2q14.3.

Key structural features:

• Protein C contains γ-carboxyglutamic acid (Gla) residues — these are formed by vitamin K–dependent carboxylation and are essential for calcium-mediated binding to phospholipid surfaces
• Without vitamin K, Protein C cannot bind to membrane surfaces and therefore cannot function — this is the same reason warfarin (a vitamin K antagonist) impairs Protein C function

The activation of Protein C is dependent on: ^[1]

1. Vitamin K (for proper synthesis/γ-carboxylation)
2. Thrombin (the key activator)

The activation pathway is beautifully self-regulating:

Thrombin (IIa) + Thrombomodulin (TM, on endothelial surface)
                    ↓
            Thrombin-TM complex
                    ↓
     Activates Protein C → Activated Protein C (APC)
                    ↓
    [Enhanced by Endothelial Protein C Receptor (EPCR)]

Why is this elegant? Thrombin is the central enzyme of the coagulation cascade that promotes clotting. But when thrombin binds to thrombomodulin on intact endothelial cells, it switches roles — it now activates Protein C, which is an anticoagulant. This is one of the body's built-in negative feedback loops: the more thrombin is generated, the more Protein C is activated, putting the brakes on coagulation.

Activated Protein C inactivates clotting factors: ^[1]

• Factor Va (the cofactor that accelerates Factor Xa's conversion of prothrombin → thrombin)
• Factor VIIIa (the cofactor that accelerates Factor IXa's activation of Factor X)

APC achieves this by proteolytic cleavage of these cofactors, rendering them non-functional.

Protein S is a cofactor for activated Protein C ^[1] — it enhances APC's ability to bind phospholipid surfaces and cleave Factor Va and VIIIa. This is why Protein S deficiency produces a clinically similar (though slightly milder) phenotype.

Additionally, APC has:

• Profibrinolytic activity: APC inhibits plasminogen activator inhibitor-1 (PAI-1), thereby promoting fibrinolysis (clot breakdown)
• Anti-inflammatory and cytoprotective effects: via EPCR and protease-activated receptor-1 (PAR-1) signalling on endothelial cells

Protein C deficiency has autosomal dominant inheritance. ^[1]

Over 330 mutations in the PROC gene have been identified. These are classified into two types:

Two types of Protein C deficiency exist: Type I and Type II. ^[1]

Heterozygous Protein C deficiency:

• Protein C levels typically 30–65% of normal (normal range ~70–140%)
• Variable penetrance — not all heterozygous individuals develop thrombosis (lifetime risk ~50%)
• First VTE usually occurs between ages 10–50, often provoked by an additional risk factor (surgery, immobilisation, pregnancy, OCP use)

Homozygous or compound heterozygous Protein C deficiency:

• Protein C levels < 1% (virtually undetectable)
• Presents at birth with purpura fulminans — a devastating condition of widespread microvascular thrombosis with haemorrhagic skin necrosis
• Fatal without immediate treatment (Protein C concentrate replacement + anticoagulation)

This is actually more common in clinical practice than the inherited form. Causes include:

Under normal circumstances, levels of natural anticoagulants in our body change over time — in pregnancy, levels change in different trimesters; childhood has different reference ranges. ^[1]

The logic is straightforward:

1. Normal coagulation requires a balance between procoagulant forces (Factor Va, VIIIa, thrombin, fibrin formation) and anticoagulant forces (Protein C/S system, Antithrombin, TFPI)
2. When Protein C is deficient or dysfunctional → Factor Va and Factor VIIIa are not adequately inactivated
3. Factor Va and Factor VIIIa persist longer than they should → sustained and excessive thrombin generation
4. Excessive thrombin → excessive fibrin formation → venous thrombus formation
5. The venous system is preferentially affected (rather than arterial) because venous flow is slower and more dependent on the anticoagulant pathway to prevent stasis-related clot formation

Virchow's triad reminds us that thrombosis depends on:

1. Stasis — more prominent in veins
2. Endothelial injury — more prominent in arteries (atherosclerosis)
3. Hypercoagulability — affects both, but the clinical manifestation of inherited thrombophilia is predominantly venous

This is because:

• Arterial thrombi are primarily platelet-rich ("white thrombi") and driven by high shear stress + endothelial injury
• Venous thrombi are primarily fibrin-rich ("red thrombi") and driven by stasis + hypercoagulable states
• Since Protein C deficiency causes a hypercoagulable state (excess fibrin formation), it preferentially manifests as venous thrombosis

However, in severe cases (homozygous deficiency, combined deficiencies), arterial thrombosis and stroke can rarely occur.

In homozygous neonates with near-zero Protein C levels:

• There is essentially no endogenous brake on Factor Va/VIIIa
• Widespread microvascular thrombosis occurs throughout the body
• Skin and subcutaneous tissue are particularly vulnerable due to their end-artery blood supply
• Microvascular thrombosis → ischaemic necrosis of the skin → the characteristic dark purple/black haemorrhagic skin lesions = purpura fulminans ("purpura" = purple spots; "fulminans" = rapid/fulminant onset)
• The same pathological process occurs in DIC-associated purpura fulminans (e.g. meningococcal sepsis) where Protein C is consumed

In DIC, purpura fulminans is due to Protein C deficiency (consumption). ^[2]

An important concept to understand alongside Protein C deficiency is Activated Protein C Resistance (APCR):

• Factor V Leiden is a point mutation (R506Q) in Factor V that makes it resistant to cleavage by APC
• The net effect is functionally identical to Protein C deficiency: Factor Va persists and drives excess thrombin generation
• Factor V Leiden is the most common inherited thrombophilia in Caucasians (~5% prevalence) but is extremely rare in Chinese/East Asian populations
• When a patient has both Protein C deficiency AND Factor V Leiden (compound heterozygosity), the risk of thrombosis is synergistically increased

Thrombophilia screening tests include: Protein C, Protein S, activated Protein C resistance (APCR), anti-thrombin (AT), Factor V Leiden PCR, Prothrombin G20210A mutation, and APLS markers (anti-cardiolipin, lupus anticoagulant, anti-β2-glycoprotein I antibody). ^[2]

It is important to understand the pattern of bleeding vs. thrombosis:

• Protein C deficiency causes a thrombotic tendency, NOT a bleeding tendency
• Patients do not present with mucocutaneous bleeding, petechiae (unless DIC supervenes), haemarthrosis, or prolonged bleeding after tooth extraction
• The platelet count, PT, and APTT are typically normal in isolated Protein C deficiency
• This is fundamentally different from haemophilia or vWD, which cause a bleeding tendency

Indications for thrombophilia screening include: ^[2]

• Young patients with idiopathic (unprovoked) venous thrombosis
• Suspected APLS, e.g. recurrent miscarriage
• Unusual sites of thrombosis, e.g. mesenteric, renal, portal vein, cerebral venous sinus
• Warfarin-induced skin necrosis (Protein C/S deficiency)

Do not test at the time of the VTE event, or while patients are receiving anticoagulants (withhold warfarin × 2 weeks, DOAC × at least 2 days). ^[2]

Why?

• Acute thrombosis → all three natural anticoagulants are consumed in the clot → falsely low levels ^[1]
• Warfarin reduces Protein C (vitamin K–dependent) → false positive for deficiency
• Heparin reduces antithrombin levels → false positive for AT deficiency
• DOACs may interfere with clot-based assays (especially lupus anticoagulant testing)
• Best to test at least 2–4 weeks after the acute event and after discontinuation of anticoagulants for appropriate durations

Tests include: ^[2]

• Protein C (activity and antigen levels)
• Protein S (total and free — the free form is what we look at) ^[1]
• Activated Protein C Resistance (APCR)
• Antithrombin (AT) activity
• Factor V Leiden PCR
• Prothrombin G20210A mutation
• APLS markers: Anti-cardiolipin antibody, Lupus anticoagulant, Anti-β2-glycoprotein I antibody

This means that standard coagulation screening (PT, APTT) will NOT detect Protein C deficiency — you must specifically order Protein C levels.

Recall from lectures:

• Extrinsic pathway: Tissue Factor (III) → activates Factor VII → Factor VIIa/TF complex → activates Factor X
• Intrinsic pathway: Factor XII → XI → IX (with VIIIa as cofactor) → activates Factor X
• Common pathway: Factor Xa (with Va as cofactor) → converts Prothrombin (II) → Thrombin (IIa) → Fibrinogen (I) → Fibrin

Vitamin K assists in the enzymatic formation of clotting factors II, VII, IX, X, Protein C and S. ^[3]

Protein C (when activated) targets:

• Factor Va — the cofactor of the prothrombinase complex (common pathway)
• Factor VIIIa — the cofactor of the tenase complex (intrinsic pathway)

By removing both cofactors, APC shuts down thrombin generation at two critical amplification steps.

These are all conditions where there is a genetic defect in one of the body's natural anticoagulant or fibrinolytic pathways. They share certain features: autosomal dominant inheritance (except rare homozygous states), predilection for venous thrombosis, and presentation at a young age.

The diagnosis rests on measuring Protein C activity (a functional/chromogenic assay) and Protein C antigen (an immunological assay). Together these allow both diagnosis and typing.

Important caveats:

• Levels change throughout life — in pregnancy, levels change in different trimesters; childhood has different reference ranges ^[1]
• Neonates physiologically have ~30–40% Protein C activity at birth (reaches adult levels by ~6 months)
• Mild heterozygous deficiency may overlap with the lower end of the normal range → this is why repeat testing and family studies are essential

Thrombophilia screening indications: ^[2]

• Young patients with idiopathic venous thrombosis
• Suspected APLS, e.g. recurrent miscarriage
• Unusual sites of thrombosis, e.g. mesenteric, renal, portal vein, cerebral venous sinus
• Warfarin-induced skin necrosis (Protein C/S deficiency)

Timing: Do not test at time of VTE event, or while patients are receiving anticoagulants (withhold warfarin × 2 weeks, DOAC × at least 2 days). ^[2]

Which assay to order first? Always start with Protein C activity (chromogenic) — it is the most sensitive and least prone to interference. Only if activity is low, proceed to Protein C antigen for typing.

Thrombophilia screening tests include: Protein C, Protein S, activated protein C resistance (APCR), anti-thrombin (AT), Factor V Leiden PCR, Prothrombin G20210A mutation, and APLS markers (anti-cardiolipin, lupus anticoagulant, anti-β2-glycoprotein I antibody). ^[2]

These are the routine bedside coagulation tests. It is critical to understand that Protein C deficiency does NOT affect standard coagulation tests in isolation.

You can do well on just platelet count, PT and APTT ^[15] — but for Protein C deficiency specifically, these will all be normal. You must specifically order Protein C levels; routine coagulation screening will miss the diagnosis entirely.

When a patient with Protein C deficiency presents with suspected VTE, the following investigations are needed to detect and characterise the thrombotic event:

A mixing study (1:1 mix of patient plasma with normal pooled plasma) is primarily used to evaluate prolonged PT or APTT — which, as we've established, are normal in isolated Protein C deficiency. Therefore, a mixing study is not directly relevant for diagnosing Protein C deficiency itself.

However, it is useful in the broader thrombophilia workup:

• Mixing study corrects the APTT → factor deficiency (e.g. haemophilia, vWD) ^[8]
• Mixing study does NOT correct the APTT → inhibitor present (e.g. lupus anticoagulant — which causes APTT prolongation but thrombotic tendency in vivo) ^[8]

This helps differentiate APLS (an acquired thrombophilia in the DDx of Protein C deficiency) from factor deficiencies.

Heparin works by enhancing antithrombin activity. This is why antithrombin deficiency results in VTE often resistant to normal doses of heparin ^[11] — but in Protein C deficiency, heparin responsiveness is normal because antithrombin is intact.

If a Protein C–deficient patient presents with massive PE (sBP < 90 mmHg or drop ≥ 40 mmHg from baseline):

• No time for risk stratification — go for TTE (RV dilatation, loss of function, clot-in-transit) and order CTPA ^[19]
• Start heparin immediately while awaiting imaging ^[19]
• Thrombolysis: systemic thrombolysis with alteplase (rtPA) if no contraindications
  • Standard PE dose: alteplase 100 mg IV over 2 hours (or 0.6 mg/kg over 15 min as accelerated regimen, max 50 mg)
  • Contraindications to thrombolysis include: previous haemorrhagic stroke, active bleeding, suspected aortic dissection, intracranial neoplasm, recent intracranial/spinal surgery ^[20]
• Surgical/interventional thrombectomy: if thrombolysis is contraindicated or fails
• ICU admission for haemodynamic and respiratory support
  • Give high-flow nasal cannula oxygen rather than positive pressure ventilation → positive pressure increases RV afterload ^[19]

DOACs have become the preferred first-line agents for VTE treatment in most patients, including those with inherited thrombophilia (Protein C deficiency).

Key advantages of DOACs over warfarin in Protein C deficiency:

• No risk of warfarin-induced skin necrosis — DOACs do not affect vitamin K–dependent protein synthesis, so they do not create the transient hypercoagulable state that warfarin does
• Fixed dosing, no routine INR monitoring, fewer drug–food interactions
• Rivaroxaban and apixaban can be started without heparin bridging (they have rapid onset of action with a "lead-in" high-dose phase)

Contraindications/limitations of DOACs:

Warfarin is a vitamin K antagonist → reduces factors II, VII, IX, X ^[21]

Warfarin remains a valid option for long-term anticoagulation in Protein C deficiency, but requires special precautions due to the risk of warfarin-induced skin necrosis.

Pregnancy is a uniquely challenging situation because:

• Pregnancy itself is a hypercoagulable state (↑ fibrinogen, ↑ Factor VII, VIII, vWF; ↓ Protein S; ↓ fibrinolysis; venous stasis from uterine compression) ^[17]
• Warfarin crosses the placenta → risk of fetal ICH and teratogenicity ^[17]
• DOACs are contraindicated in pregnancy (cross placenta, insufficient safety data)
• LMWH is the only safe anticoagulant in pregnancy

This is the feared complication that specifically points to Protein C (or Protein S) deficiency.

This is a haematological emergency in neonates.

Patients on long-term anticoagulation for Protein C deficiency may experience bleeding complications. Know the reversal agents:

This is both a complication of the disease AND a complication of treatment — it occurs specifically because of the interaction between Protein C deficiency and warfarin therapy.

Warfarin-induced skin necrosis is associated with Protein C/S deficiency — this is a classic thrombophilia screening indication ^[2].

Purpura fulminans is due to Protein C deficiency ^[2] — this can occur in homozygous inherited deficiency OR in acquired severe Protein C deficiency (e.g. DIC from meningococcal sepsis).

Warfarin has a notoriously narrow therapeutic index and is subject to numerous drug and dietary interactions — this is especially relevant for patients on lifelong therapy.

DOACs have fewer (but not zero) drug interactions — notable interactions include strong CYP3A4/P-glycoprotein inhibitors and inducers.

Hereditary Protein C deficiency is listed as a cause of DIC ^[25]. The mechanism:

• Severe Protein C deficiency (especially homozygous) → unchecked thrombin generation → widespread microvascular thrombosis → consumption of clotting factors, platelets, and natural anticoagulants → classic DIC picture (↑PT, ↑APTT, ↓fibrinogen, ↑D-dimer, ↓platelets, schistocytes on PBS) ^[2]

This is the mechanism behind neonatal purpura fulminans and can also occur in severely acquired Protein C deficiency (e.g. meningococcal sepsis).

DIC organ dysfunction includes: AKI, liver dysfunction (jaundice), acute lung injury (pulmonary haemorrhage, ARDS), neurological dysfunction (coma, delirium), adrenal failure (Waterhouse-Friderichsen syndrome) ^[2]

Protein C deficiency rarely exists in isolation — it commonly interacts with acquired risk factors to precipitate VTE: