Contents · 12 sections
In a nutshell. Hemostasis is a three-stage system to stop bleeding: primary (vascular spasm + platelet plug via vWF and GPIb/IIb-IIIa), secondary (coagulation cascade: extrinsic pathway → TF/VIIa, intrinsic pathway → XII/XI/IX/VIII, common pathway → X/V → thrombin → fibrin), and fibrinolysis (plasmin from plasminogen). Laboratory tests: PT/INR — extrinsic pathway, APTT — intrinsic pathway, D-dimer — fibrinolysis. Disorders: von Willebrand disease, hemophilia A (VIII) and B (IX), DIC, thrombophilias (Leiden, prothrombin G20210A, AT/PC/PS deficiency).
1. Primary hemostasis
- Vascular spasm — reflex-mediated, occurs within the first seconds after injury.
- Platelet adhesion: subendothelial collagen → von Willebrand factor (vWF) → GPIb receptor on platelets.
- Platelet activation: release of dense granule contents (ADP, serotonin), α-granules (fibrinogen, vWF), synthesis of TxA2.
- Aggregation: GPIIb/IIIa receptor binds fibrinogen, platelets are «cross-linked» together.
- Result — «white» platelet plug; sufficient for small vessels.
2. Secondary hemostasis — cascade
- Coagulation cascade — cascade proteolysis of clotting factors (mainly serine proteases).
- Extrinsic pathway: tissue factor (TF, III) + VIIa → activation of X.
- Intrinsic pathway: contact with a negative surface → XII → XI → IX + VIII → X.
- Common pathway: Xa + Va → prothrombin (II) → thrombin (IIa) → fibrinogen (I) → fibrin.
- XIIIa — cross-links fibrin strands into a stable polymer.
- Modern model (cell-based): initiation (TF/VIIa) → amplification (thrombin activates V, VIII, XI, platelets) → propagation (massive thrombin burst).
3. Clotting factors
| Factor | Name | Synthesis | Feature |
|---|---|---|---|
| I | Fibrinogen | Liver | Acute-phase |
| II | Prothrombin | Liver | Vitamin K-dependent |
| III | Tissue factor | Endothelium, fibroblasts | Extrinsic pathway trigger |
| IV | Ca²⁺ | — | Cofactor |
| V | Proaccelerin | Liver | Leiden mutation → thrombophilia |
| VII | Proconvertin | Liver | Vit K; shortest T½ (~6 h) |
| VIII | Antihemophilic | Endothelium | Hemophilia A |
| IX | Christmas | Liver | Vit K; hemophilia B |
| X | Stuart-Prower | Liver | Vit K |
| XI | PTA | Liver | Hemophilia C (Rosenthal) |
| XII | Hageman | Liver | Deficiency does not cause bleeding |
| XIII | Fibrin-stabilizing | Liver | Fibrin cross-linking |
| vWF | von Willebrand | Endothelium, megakaryocytes | Adhesion + factor VIII carrier |
4. Vitamin K-dependent factors
- II, VII, IX, X + anticoagulant proteins C and S.
- Vitamin K is a cofactor for γ-glutamyl carboxylase, adding γ-carboxyglutamate residues necessary for Ca²⁺ binding.
- Warfarin blocks epoxide reductase (VKORC1) → inactive factors.
- Newborns and antibacterial therapy → vitamin K deficiency → hemorrhagic disease.
- Warfarin antidote — vitamin K1 (phytomenadione) + FFP or prothrombin complex concentrate (PCC) for severe bleeding.
5. Natural anticoagulants
- Antithrombin III — main inhibitor of thrombin and Xa; heparin enhances its effect 1000-fold.
- Protein C (+ protein S cofactor) — inactivates Va and VIIIa; activated by thrombomodulin on the endothelium.
- TFPI (tissue factor pathway inhibitor) — inhibits VIIa/TF.
- Endothelial heparan sulfate — endogenous heparin-like substance.
- Deficiencies: AT III, protein C and S — hereditary thrombophilias.
6. Fibrinolysis
- Plasminogen → plasmin (acted upon by tPA — endothelium, or urokinase).
- Plasmin breaks down fibrin → fibrin degradation products (FDP), including D-dimer.
- Inhibitors: α2-antiplasmin (inactivates plasmin), PAI-1 (tPA inhibitor).
- Clinically: tPA/alteplase — thrombolysis for MI, ischemic stroke, PE.
- Tranexamic acid, aminocaproic acid — antifibrinolytics for bleeding.
7. Laboratory monitoring
| Parameter | Normal | What it reflects |
|---|---|---|
| PT / INR | 11–15 s / 0.8–1.2 | Extrinsic + common pathway; vit K, liver, warfarin |
| aPTT | 25–35 s | Intrinsic + common; heparin, hemophilias |
| Thrombin time | 15–18 s | Fibrinogen → fibrin |
| Fibrinogen | 2–4 g/L | Acute-phase reactant; ↓ in DIC |
| D-dimer | < 500 ng/mL | Fibrinolysis; ↑ VTE, DIC |
| Anti-Xa | 0.6–1.0 IU/mL (LMWH) | Heparin monitoring |
| Platelets | 150–400 × 10⁹/L | Primary hemostasis |
| Ivy bleeding time | 2–7 min | Platelet function + vW |
| TEG/ROTEM | — | Integral coagulation assessment |
8. Hereditary coagulopathies
- Hemophilia A — factor VIII deficiency, X-linked recessive; hemarthrosis, muscle hematomas.
- Hemophilia B (Christmas disease) — factor IX deficiency; clinically similar to A.
- Von Willebrand disease — most common inherited, autosomal dominant; mucocutaneous bleeding, prolonged bleeding time, ↑ aPTT.
- Treatment: recombinant VIII, IX; vWF/VIII concentrates; DDAVP — enhances vWF release in mild VWD.
- Factor VIII inhibitors — antibodies in 20–30% of patients with severe hemophilia A → use of FEIBA, rFVIIa, emicizumab.
9. Thrombophilias
- Factor V Leiden (Arg506Gln mutation) — resistance to activated protein C; most common.
- Prothrombin G20210A mutation — ↑ plasma prothrombin.
- AT III, protein C, protein S deficiency.
- Antiphospholipid syndrome — antibodies to β2-glycoprotein I, cardiolipin, lupus anticoagulant; arterial and venous thrombosis, recurrent pregnancy loss.
- Hyperhomocysteinemia.
- Screening indicated for: VTE under 50, unprovoked VTE, recurrent pregnancy loss, family history.
10. Acquired disorders
- DIC — generalized activation of clotting + fibrinolysis; sepsis, obstetric catastrophes, malignancy, trauma.
- DIC laboratory findings: ↑ D-dimer, ↓ fibrinogen, ↓ platelets, prolonged PT/aPTT.
- Liver failure — impaired synthesis of all factors except VIII.
- Vitamin K deficiency — in newborns, chronic diarrhea, malabsorption, antibiotics.
- Massive transfusion — dilutional coagulopathy.
- Heparin-induced thrombocytopenia (HIT) — antibodies to PF4-heparin → paradoxical thrombosis.
11. Anticoagulants and antiplatelet agents
- UFH (unfractionated heparin) — potentiates AT III, inhibits IIa and Xa; aPTT monitoring.
- LMWH (enoxaparin, nadroparin) — predominantly anti-Xa; anti-Xa monitoring.
- Fondaparinux — selective anti-Xa; does not cause HIT.
- Warfarin — VKORC1; INR monitoring (target 2.0–3.0 or 2.5–3.5 for a mechanical heart valve).
- DOACs: dabigatran (direct thrombin inhibitor), rivaroxaban/apixaban/edoxaban (direct Xa inhibitors). Antidotes: idarucizumab (dabigatran), andexanet alfa (Xa inhibitors).
- Antiplatelet agents: aspirin (COX-1 → blocks TxA2), clopidogrel/ticagrelor/prasugrel (P2Y12), abciximab/tirofiban (GPIIb/IIIa).
12. FAQ
Why do patients with factor XII deficiency not bleed?
Factor XII plays a minimal role in vivo — coagulation is initiated via the extrinsic pathway (TF/VIIa). Factor XII deficiency is only evident in vitro (↑ aPTT) and is clinically asymptomatic.
What is the difference between a "white" and a "red" thrombus?
White — platelet-rich, in high-flow arteries (ACS). Red — fibrin + RBCs, in low-flow veins (VTE). Hence — antiplatelet agents for arterial thrombosis, anticoagulants for venous thrombosis.
Why is D-dimer "poor" for diagnosing PE, but good for ruling it out?
High sensitivity (> 95 %) → a negative result reliably rules out PE in patients with low pretest probability. However, specificity is low — ↑ in many conditions (sepsis, surgery, malignancy, pregnancy).
How to rapidly reverse warfarin before surgery?
Stop 5 days prior, check INR the day before; in high thrombotic risk (mechanical valve, recent VTE) — LMWH "bridging" with the last dose given 24 hours before surgery.
Why is factor VIII elevated in liver failure while other factors are reduced?
Factor VIII is synthesized not only in the liver but also in the endothelium (as an acute-phase reactant). Other vitamin K-dependent factors (II, VII, IX, X) and fibrinogen are synthesized exclusively in hepatocytes, hence they are deficient in liver pathology.
See also: DIC · Hemophilia · PE · Anticoagulant therapy · Hematology Catalog