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Hemostasis & Coagulation Cascade

Name: Hemostasis & Coagulation Cascade
Creator: Veli Bakalov, MD

Platelet plug to fibrin mesh, and decoding PT vs PTT

Hematology & Oncology·Hemostasis & Thrombosis·5 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Primary hemostasis = platelet plug: vWF links GpIb to collagen (adhesion), ADP and TXA2 activate, fibrinogen bridges GpIIb/IIIa (aggregation); secondary hemostasis = fibrin mesh from the cascade.
Aspirin blocks COX-1 (no TXA2), clopidogrel blocks the P2Y12 ADP receptor, and abciximab blocks GpIIb/IIIa.
vWF comes from endothelial Weibel-Palade bodies and platelet α granules and also carries factor VIII, so vWF deficiency can prolong the PTT.
PT = extrinsic (TF–VII) plus common pathway and monitors warfarin; factor VII's short half-life makes the PT rise first in warfarin use, vitamin K deficiency and liver disease.
PTT = intrinsic (XII, XI, IX, VIII) plus common pathway and monitors heparin; factor XII deficiency prolongs the PTT without bleeding, and factor XIII deficiency bleeds with normal PT and PTT.
Both PT and PTT prolonged: common pathway (X, V, II, fibrinogen), DIC, severe liver disease, vitamin K deficiency or DOACs.
Thrombin is procoagulant alone but activates protein C when bound to thrombomodulin; APC with protein S inactivates Va and VIIIa, and factor V Leiden resists this.
Heparin accelerates antithrombin (IIa, IXa, Xa, XIa, XIIa) about 1000-fold; antithrombin deficiency causes heparin resistance, and protein C/S deficiency predisposes to warfarin skin necrosis.
tPA converts plasminogen to plasmin, which lyses fibrin into D-dimers; tranexamic and aminocaproic acid block fibrinolysis; Virchow's triad = endothelial injury, stasis, hypercoagulability.

Primary hemostasis: the platelet plug

Two phases. Primary hemostasis forms a weak platelet plug (platelets, vWF, GpIb, GpIIb/IIIa). Secondary hemostasis activates the coagulation cascade to generate thrombin and a fibrin mesh that stabilizes the plug. Both must work, and defects in each give a distinct bleeding pattern.

AdhesionvWF bridges platelet GpIb to exposed subendothelial collagen
ActivationPlatelets change shape and release ADP and TXA₂, upregulating GpIIb/IIIa
AggregationFibrinogen crosslinks GpIIb/IIIa receptors on neighboring platelets

Antiplatelet targets. Aspirin irreversibly blocks COX-1, so no TXA₂ is made; clopidogrel blocks the P2Y12 ADP receptor; abciximab blocks GpIIb/IIIa.

von Willebrand factor (vWF). Made by endothelium (stored in Weibel-Palade bodies) and by megakaryocytes (platelet α granules), vWF has two jobs: it links platelet GpIb to collagen for adhesion, AND it carries and stabilizes factor VIII in the circulation. That is why vWF deficiency also lowers factor VIII and can prolong the PTT.

Primary vs secondary hemostasis defects

Feature	Primary (platelet plug)	Secondary (coagulation factors)
Components	Platelets, vWF, GpIb, GpIIb/IIIa	Clotting factors, thrombin, fibrin
Bleeding pattern	Mucocutaneous: petechiae, epistaxis, gum bleeding, menorrhagia	Deep: hemarthroses, muscle hematomas, delayed post-surgical bleeding
Screening labs	Platelet count, platelet function	PT, PTT
Examples	Thrombocytopenia, von Willebrand disease, aspirin	Hemophilia A and B, vitamin K deficiency, warfarin

The coagulation cascade

Extrinsic pathway. Tissue factor (factor III) from injured cells activates factor VII, which activates factor X. The PT measures the extrinsic plus common pathways and monitors WARFARIN. Factor VII has the SHORTEST half-life, so the PT rises first with warfarin, vitamin K deficiency and liver disease.

Intrinsic pathway. Contact activation of factor XII leads to XI and then IX, which with factor VIII activates factor X. The PTT measures the intrinsic plus common pathways and monitors HEPARIN. Deficiency of VIII (hemophilia A) or IX (hemophilia B) prolongs the PTT; factor XII deficiency prolongs the PTT but does NOT cause bleeding. Memory aid: intrinsic has many factors (12, 11, 9, 8), the "long" PTT; extrinsic has one (7), the PT.

Common pathway. Both arms converge on factor X, which with factor V forms prothrombinase, converting prothrombin (II) to thrombin (IIa). Thrombin cleaves fibrinogen (I) to fibrin, and factor XIII crosslinks it into a stable mesh. Factors X, V, II and fibrinogen form the common pathway, probed by both PT and PTT. Factor XIII deficiency causes bleeding with a NORMAL PT and PTT.

Vitamin K–dependent factors. Factors II, VII, IX and X and proteins C and S require vitamin K–dependent γ-carboxylation to bind calcium on phospholipid surfaces. Warfarin blocks vitamin K epoxide reductase, preventing vitamin K recycling.

Thrombin is the master switch. Thrombin is procoagulant: it cleaves fibrinogen to fibrin and activates platelets and factors V, VIII, XI and XIII, amplifying its own production. When it binds endothelial THROMBOMODULIN, it instead activates protein C and becomes anticoagulant. This dual role keeps clotting localized to the injury.

Reading PT and PTT

Localizing a coagulation defect

Pattern	Localization	Typical causes
Isolated ↑PT	Extrinsic (factor VII)	Early warfarin, early vitamin K deficiency, liver disease
Isolated ↑PTT	Intrinsic (VIII, IX, XI, XII)	Hemophilia A or B, von Willebrand disease, heparin
Both ↑	Common pathway (X, V, II, fibrinogen) or several factors	DIC, severe liver disease, vitamin K deficiency, DOACs
Both normal, yet bleeding	Platelets or factor XIII	Thrombocytopenia, platelet dysfunction, factor XIII deficiency

Mixing study. Mixing patient plasma 1:1 with normal plasma separates a factor deficiency, in which a prolonged PTT corrects, from an inhibitor such as a factor VIII antibody or lupus anticoagulant, in which it does not. Lifelong hemarthroses with an isolated PTT that corrects on mixing points to hemophilia.

Natural anticoagulants and fibrinolysis

Antithrombin. Antithrombin inactivates thrombin (IIa) and factors IXa, Xa, XIa and XIIa. Heparin binds antithrombin and accelerates it about 1000-fold. In antithrombin deficiency (inherited, or acquired by urinary loss in nephrotic syndrome), heparin fails to adequately prolong the PTT: heparin resistance.

Proteins C and S. Thrombin–thrombomodulin activates protein C, and protein S is its cofactor. Activated protein C (APC) proteolytically inactivates factors Va and VIIIa, dampening the cascade. In factor V Leiden, the most common inherited thrombophilia, factor Va resists this cleavage (APC resistance). Protein C has a short half-life, so warfarin lowers it before the procoagulant factors, causing a transient hypercoagulable state; in protein C or S deficiency this can cause warfarin-induced skin necrosis, which is why heparin bridges the start of warfarin.

Fibrinolysis. Tissue plasminogen activator (tPA) converts plasminogen to PLASMIN, which cleaves fibrin into fibrin degradation products and D-dimers, a marker of cross-linked fibrin lysis. α₂-Antiplasmin inhibits plasmin. tPA drugs lyse clots; aminocaproic acid and tranexamic acid inhibit fibrinolysis.

Brakes on clotting

Regulator	Action	Clinical link
Antithrombin	Inactivates IIa, IXa, Xa, XIa, XIIa	Heparin's target; deficiency → heparin resistance
Thrombomodulin	Binds thrombin so it activates protein C	Turns thrombin into an anticoagulant
Protein C + S	Inactivate Va and VIIIa	Factor V Leiden resists; warfarin skin necrosis
Plasmin (via tPA)	Degrades fibrin → D-dimers	Alteplase lyses clots; tranexamic acid blocks

Endothelium and thrombosis

Healthy endothelium is anticoagulant. Intact endothelium actively prevents clotting: it releases prostacyclin (PGI₂) and nitric oxide, which vasodilate and inhibit platelets; expresses thrombomodulin and heparin-like molecules; and secretes tPA. Injury exposes collagen and tissue factor, flipping the surface to procoagulant to launch hemostasis.

Virchow's triad. Thrombosis arises from endothelial injury (atherosclerosis, trauma, surgery), stasis (atrial fibrillation, immobility, long flights) and hypercoagulability (factor V Leiden, malignancy, oral contraceptives, nephrotic syndrome). A postoperative, immobilized patient taking estrogen combines all three. Arterial thrombi form under high flow and are platelet-rich ("white"); venous thrombi form in stasis and are fibrin- and RBC-rich ("red"). Lines of Zahn, alternating layers of platelets/fibrin and RBCs, show that a thrombus formed in flowing blood before death.