Introduction to Bleeding Disorders

Title slide with large red text on the left and a microscopic image of red blood cells flowing on the right.

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HK

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Objectives

Physiology of hemostasis
Hemostasis : Process of clot formation
Classification of bleeding disorders
Clinical approach to bleeding disorders
- Case study -1 ( hereditary bleeding disorder)
- Case study -2 ( acquired bleeding disorder)
Interpretation of coagulation tests (?)

The Hemostatic System

A balance diagram: on the Clot Formation side, three overlapping circles labeled Coagulation, Platelets, and Endothelium. On the Clot Prevention side, two circles labeled Fibrinolysis and Anti-Coagulation. The beam balances Clot Formation against Clot Prevention.

Bleeding tendency = hemophilia = hypo-coagulable state

Thrombosis tendency = thrombophilia = hypercoagulable state

Left: an epigraph and a red-highlighted list of hemostasis phases. Right: Figure 24.1 flowchart from vessel injury through platelet and coagulation steps to a stable haemostatic plug.

03 / 13

Blood is the essence of vitality; it must remain in constant motion to sustain every part of the body. When blood ceases to flow, life ends.

Interrelated process

STOP ( natural anticoagulants)
START ( endothelium + platelets) — Platelet plug
MAKE ( coagulation cascade) — Fibrin clot
STOP ( natural anticoagulants)
CLEAN ( fibrin-o-lysis)

Figure 24.1 (flowchart logic): Vessel injury leads to Collagen exposure and Tissue factor. Collagen exposure → Platelet adhesion → Platelet activation (Shape change, granule secretion and activation of GPIIb/IIIa). Platelet activation releases Serotonin → Vasoconstriction → Reduced blood flow, and Thromboxane A₂, ADP → Platelet aggregation → Primary haemostatic plug. Platelet phospholipid and Tissue factor feed the Blood coagulation cascade → Thrombin → Fibrin. Both the Primary haemostatic plug and Fibrin converge to form the Stable haemostatic plug.

Figure 24.1 The involvement of blood vessels, platelets and blood coagulation in haemostasis. ADP, adenosine diphosphate.

Left: red-highlighted phase list. Right: Figure 35.1 cartoon showing anticoagulant functions of intact endothelial cells (top) and procoagulant functions of damaged endothelial cells (bottom) around a central row of hemostatic components.

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Hemostasis is a process

START ( endothelium + platelets) — Platelet plug
MAKE ( coagulation cascade) — Fibrin clot
STOP ( natural anticoagulants)
CLEAN ( fibrin-o-lysis)

Central sequence of the hemostatic system: ECs → Platelets → Coagulation → Fibrinolysis.

Anticoagulant Functions of Intact Endothelial Cells: Smooth, EC lining; PGI₂; Nitrous oxide; Heparan sulfate; TFPI; Thrombo-modulin; EPCR; TPA.

Procoagulant Functions of Damaged Endothelial Cells: Vasoconstriction; VWF; ADAMTS13; P-Selectin; Collagen exposed; TF exposed; PAI-1; TAFI.

Figure 35.1 Hemostatic Properties of Endothelial Cells that Line the Inner Surface of All Blood Vessels. Depicted in this cartoon are the anticoagulant properties associated with normal intact endothelial cells and the procoagulant properties associated with damaged endothelial cells as they relate to the functions of the hemostatic system listed in the center. ADAMTS13, A disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13; ECs, endothelial cells; EPCR, endothelial cell protein C receptor; PAI-1, plasminogen activator inhibitor-1; PGI₂, prostacyclin or prostaglandin I₂; TAFI, thrombin activatable fibrinolysis inhibitor; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TPA, tissue plasminogen activator; VWF, von Willebrand factor.

Left: highlighted text listing platelet activation steps. Right: a Platelet Adhesion and Aggregation diagram and a central platelet showing its glycoprotein receptors with their targets and activities.

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START

Endothelial injury → release of TF , Collagen

Vascular muscle contraction

Platelet's activations →

Adhesion ( vWF, Collagen)
Aggregation (Fibrinogen)
Secretion (Ca++, ADP, serotonin, etc) + PL

Set the stage for the Make (ing ) of the clot

III = Tissue factor = thromboplastin

PL= Phospholipid

Platelet Adhesion and Aggregation

Diagram legend: von Willebrand factor; Fibrinogen. Steps shown across the subendothelium: Endothelial cell → Collagen-laden subendothelium → Platelet adhesion (via GpIb) → Activated GpIIb/IIIa → Tissue factor, with the Coagulation cascade (IIa) building a Fibrin mesh.

Platelet glycoprotein receptors and their targets/activities:

GPIb — Target: von Willebrand factor; Activity: Adhesion
GPIa-IIa — Target: Collagen; Activity: Adhesion
GPIIb-IIIa — Target: Fibrinogen (Factor I); Activity: Aggregation
GPVI — Target: Collagen; Activity: Activation

Three images: an illustration of a clot with red cells and fibrin strands, a scanning electron micrograph of a fibrin mesh with trapped cells (scale 10.0U), and photomicrograph of platelets aggregating.

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Platelet plug

Three visuals of clot formation:

Illustration of a forming clot with red blood cells trapped in a fibrin network.
Scanning electron micrograph of a fibrin mesh entrapping blood cells (scale bar 10.0U).
Photomicrograph captioned: "Platelets come together to form a platelet plug".

Left: bullet list and yellow box of numbered steps; an orange box at the bottom. Right: classic Y-shaped cascade diagram with intrinsic, extrinsic and common pathways labeled with PTT/ACT and PT.

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Make the clot (old theory)

Platelets plug is not enough.
This stage happens at the platelets plug surface
Activations of coagulation factors /co-factors
X:V activate prothrombin
Prothrombin (II) → Thrombin (IIa)
Fibrinogen(I) → Fibrin clot

Yellow box:

TF + FVII
TF:FVIIa activate X in presence of V
X:V activate prothrombin
Thrombin convert Fibrinogen into fibrin clot

Orange box:

Contact system → XII+XI (12+11) → IX + VIII (8+9) → X:V
X:V (5;10) activate prothrombin
Thrombin convert Fibrinogen into fibrin clot (2:1)

Cascade diagram logic: Intrinsic pathway (measured by PTT / ACT): XII → XIIa → XI → XIa → IX → IXa (with VIIIa, Ca⁺⁺, PL). Extrinsic pathway (measured by PT): Tissue factor → VII → VIIa. Both converge on the Common pathway: X → Xa (with Va, Ca⁺⁺, PL) → Prothrombin → Thrombin → Fibrinogen → Fibrin.

Left: bullet list with a large red question mark and a red circular-loop arrow. Right: cell-based coagulation diagram labeled INITIATION, PROPAGATION and AMPLIFICATION ending in insoluble cross-linked fibrin; large yellow box of numbered steps below.

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Make the clot ( new )

Loop reaction
This stage happens at the platelets plug surface
X:V activate prothrombin
Prothrombin (II) → Thrombin (IIa) — Not enough
Fibrinogen(I) → Fibrin clot
Instead, thrombin will activate more Factor V , VIII and IX

Yellow box:

TF + FVII
TF:FVIIa activate X in presence of V
X:V activate prothrombin
Thrombin not enough to convert Fibrinogen into fibrin clot
So we need an AMPLIFICATION phase….Thrombin → intrinsic pathway(8,9)—COMMON→ THROMBIN BURST

Cell-based cascade diagram logic: INITIATION — Tissue Factor + FVIIa form the TF-VIIa complex. PROPAGATION / AMPLIFICATION — Contact Factors (HMWK, Prekallikrein); FXII → FXIIa; FXI → FXIa (Ca²⁺); FIX → FIXa; FVIII → FVIIIa (Ca²⁺ + PL); FX → FXa; FV → FVa (Ca²⁺ + PL); Prothrombin (FII) → Thrombin (FIIa). Thrombin feeds back to amplify FVIII, FIX, FV. Fibrin Clot Formation and Stabilization: Fibrinogen → Soluble Fibrin → (via FXIIIa) Insoluble Cross-Linked Fibrin.

Left: simplified factor lists including Vitamin K factors. Right: colored cascade diagram (Corbett et al, 2020) showing extrinsic/intrinsic/common pathways with PT/INR, aPTT, Warfarin and Boomslang venon annotations.

09 / 13

Coagulation simplified

Vitamin K ( 1972) :
- 10,9,7,2
(8) 9, 10 [ (5) ] 7 (3)
2 (Prothrombin) → 2a ( thrombin)
1 ( fibrinogen) → 1a ( fibrin)

Cascade diagram (C. Corbett et all, 2020) logic: Extrinsic pathway — Tissue factor → VII (measured by PT/INR; Warfarin acts here). Intrinsic pathway — XII → XI → IX (with VIII) (measured by aPTT). Both converge on the Common pathway: X (with V, Ca²⁺, Lipids) → Thrombin (II) → Fibrinogen (I) → (via XIII) Fibrin mesh. Boomslang venom acts on Factor X.

Left: Y-shaped intrinsic/extrinsic/common pathway cascade diagram. Right: Table 8.1 listing coagulation factors I through XIII plus Fitzgerald and Fletcher factors, with a large red X mark beside it.

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Coagulation cascade (Table 8.1 Blood coagulation factors)

Cascade diagram logic: Intrinsic pathway (PTT / ACT): XII → XIIa → XI → XIa → IX → IXa (with VIIIa, Ca⁺⁺, PL). Extrinsic pathway (PT): Tissue factor → VII → VIIa. Common pathway: X → Xa (with Va, Ca⁺⁺, PL) → Prothrombin → Thrombin → Fibrinogen → Fibrin.

Table 8.1 Blood coagulation factors
Factor	Name
I	Fibrinogen
II	Prothrombin
III	Thromboplastin
IV	Calcium
V	Proaccelerin
VI	–
VII	Proconvertin
VIII	Antihaemophilic factor
IX	Christmas factor (plasma thromboplastin component)
X	Stuart–Prower factor
XI	Plasma thromboplastin antecedent
XII	Hageman factor
XIII	Fibrin-stabilizing factor
Fitzgerald factor	High-molecular-weight kininogen
Fletcher factor	Prekallikrein

(A large red X mark is placed beside the table.)

Left: red heading and a numbered list of natural anticoagulants. Right: diagram A showing the cascade (XII, VII to X, Va, Thrombin, Fibrin clot) inhibited by Protein S, Activated protein C, and Antithrombin.

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Stop ( termination phase )

Switch off the hemostasis cascade in order to limit the reaction to the site of injury

Natural anticoagulants :

TFPI ( Tissue factor pathway inhibitor )
Protein S
Protein C
Anti thrombin

Diagram A logic: XII and VII converge on X → Va → Thrombin → Fibrin clot. Inhibition points: Act. protein C (with Protein S) inhibits Va; Antithrombin inhibits Thrombin.

Left: red heading with three bullets on plasminogen activation. Right: Figure 9-4 fibrinolysis diagram with plasminogen converted to plasmin and inhibitors TAFI and PAI-1.

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Clean ( Fibrinolysis)

Activation of plasminogen
plasmin
Fibrin → FDP

Diagram logic: Plasminogen is activated to Plasmin by Urokinase / Streptokinase and by tPA. Plasmin degrades Cross-linked fibrin polymer into Fibrin degradation products. Inhibitors: TAFI inhibits the activation step; PAI-1 inhibits tPA.

Figure 9-4 Fibrinolysis. TAFI, thrombin–activatable fibrinolysis inhibitor; tPA, tissue plasminogen activator.

Figure 10-3: a schematic showing fibrinogen (D-E-D domains) converted by thrombin to fibrin monomer, polymerizing into a 2-stranded protofibril, then degraded by plasmin into a (DD)E complex and finally D-dimer and fragment E.

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Fibrin formation and degradation

Diagram logic: Fibrinogen (trinodular D–E–D structure with COOH and NH₂ termini) → (Thrombin) → Fibrin monomer (D–E–D) → (Polymerization and cross-linking) → 2-stranded protofibril → (Plasmin) → (DD)E complex → (Plasmin) → D-dimer (D–D) and Fragment E.

Figure 10-3 Fibrin formation and degradation. Fibrinogen has a trinocular structure with a central E and 2 D domains. Thrombin cleaves fibrinopeptides A and B (not depicted), located in the E domain. The resultant fibrin monomers polymerize nonenzymatically forming fibrin polymers. Factor XIIIa cross-links the D domains of nearby fibrin monomers. Plasmin degrades cross-linked fibrin, thereby generating (DD)E complexes composed of an E fragment noncovalently bound to D-dimer. With further plasmin attack, the (DD) E complex is degraded into fragment E and D-dimer.