Slides Bleeding Disorders

Bleeding Disorders
With Prof. Paul Moss
Hemnath Chan, hemnath5393@gmail.com

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Learning Outcomes
 Hemostasis is dependent on a combined response to injury from the

blood vessel, platelet and coagulation system
 A range of inherited and acquired disorders can lead to bleeding

disorders
 Vessel and platelet problems lead to purpura and bruising whereas

coagulation deficiency is characterised by bleeds into muscles and
joints

Reponse to vessel injury
• After injury the vessel can vasoconstrict to

reduce blood flow
• Platelets attach to the exposed collagen

on the vessel
• They then undergo platelet adherence and

a platelet aggregation reaction
• Coagulation factors ensure that thrombin

is generated in order to produce fibrinogen
and stabilize the clot

Platelet structure
• Platelets are shed from the cytoplasm of

megakaryocytes
• They are 3x 0.5 microns and contain dense

and alpha granules
• The major regulator of platelet production

is thrombopoietin from the liver and
kidneys
• Their main function is to form a plug in the

damaged vessel
Yousef Gargani, Crash Course Haematology and Immunology: Updated Print + eBook edition, 4th Edition, 2016, p. 58, Fig. 6.1, Mosby Ltd. (Elsevier)
Platelet reponse to vessel injury
• The platelets demonstrate
• adhesion,
• aggregation and
• release

Platelet adhesion reactions
• Adhesion occurs when von Willebrand

factor crosslinks GP1b on platelets to
subendothelial microfibrils on vessel
• This exposes GPIIb/IIIa which binds to vWF

and fibrinogen and leads to platelet
aggregation
• Platelet activation leads to release of

granules
Fig. 6.2 Platelet adhesion reactions. Von factor (vWF) binds

to damaged vessel walls via subendothelial microfibrils. vWF interacts with
platelets via GPib (calcium Ions, Ca2+, required). This leads to exposure of
GPIIb/IIIa receptor, which also binds vWF. Platelets bind directly to
subendothelial collagen (types I, II and III) via GPIa.
Martin R. Howard & Peter J Hamilton, Haematology, 4th Edition, 2013, p. 12, Fig. 6.1, Churchill Livingstone (Elsevier)
The blood coagulation cascade
• This is a biological amplification system

whereby initiation substances
proteolytically activate a cascade of
circulating precursor proteins (the
coagulation factor enzymes)
• This culminates in the generation of

thrombin
• This converts soluble fibrinogen into fibrin
• Fibrin enmeshes the platelet aggregates

and converts unstable complexes into
stable plugs

The traditional clotting cascade
The updated clotting cascade
Overview of hemostasis
Yousef A, Crash Course Haematology and Immunology: Updated Print + eBook edition, 4th Edition, 2016, p. 67, Fig. 6.13, Mosby Ltd. (Elsevier)
Tests of hemostatic function
• Full blood count
• Clotting tests
• Activated partial thromboplastin time

(APTT)
• Measures factors VIII, IX, XI and XII
• Normal clotting time is 30-40 seconds

Tests of hemostatic function
• Prothrombin time (PT)
• Measures factors VII, X, V, prothrombin and Test Proloned Proloned Low

fibrinogen. prothrom APTT fibrinogen
bin time
• Normal clotting time is 10 14 seconds Common Warfarin Heparin DIC
causes
• May be expressed as the international
normalized ratio (INR) Liver Hemophilia Severe
disease vWD liver
Vitamin K disease
deficiency
• Tests of platelet aggregometry
DIC DIC
Liver disease
Lupus
anticoagulant

Question
Which ONE of these is NOT true concerning platelet function ?
The nuclei are extruded

during the release reaction
GP1b binds to VWF to

promote adhesion
They adhere to each other

using the IIb/IIIa receptor

Vascular Disorders
Inherited
• Hereditary hemorrhagic telangiectasia
• AD inheritance, mutations in endoglin
• telangiectasia develop in skin, mucous

membranes and internal organs
Acquired
• Aging or steroids
• Henoch-Schonlein purpura
• scurvy
f.l.t.r.: Allan Y Wu et.al., A cohort of hands in women aged 60-73-years-old within 1 week post standard lipotransfer, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3477126/figure/F17/, cropped,
CC BY 2.0; Guiseppe A Latino et.al., Clinical manifestations of HHT, including pulmonary arteriovenous malformations (left) and mucocutaneous telangiectases (right),
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222286/figure/F1/,
Hemnath Chan, hemnath5393@gmail.com cropped, CC BY 4.0
Thrombocytopenia
• Increased destruction
• Immune mediated thrombocytopenia
• Ig G antibodies against platelets
• Treat: steroids, splenectomy or

thrombopoietin-receptor agonists
• Infection, Pregnancy, Drugs
• Thrombotic thrombocytopenic purpura
• Decreased production
• Bone marrow failure
J.T. Alqanatish et.al., Patient at presentation. a Knee flexion contractures and ecchymoses, b hyperkeratosis and follicular purpura with corkscrew hairs (white
arrow), https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462115/figure/Fig1/, cropped, CC BY 4.0
Thrombotic thrombocytopenic purpura
• Deficiency of ADAMTS13 metalloprotease

(congential or autoimmune) leads VWF
multimers
• Thrombocytopenia, microangiopathic
hemolytic anemia, neurologic
abnormalities, renal failure and fever
• Treat with plasma exchange
Sikander P. Surana et.al., Peripheral smear at admission showing evidence of microangiopathic hemolytic anemia with numerous schistocytes (arrows),
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3332179/figure/fig1/, CC BY 3.0 , no changes
Disorders of platelet function
• Inherited disorders
• - IIb/IIIa
• Bernard Soulier Ib
• Acquired
• Antiplatelet drugs
• Aspirin, clopidogrel
Martin R. Howard & Peter J Hamilton, Haematology, 4th Edition, 2013, p. 70, Fig. 35.1, Churchill Livingstone (Elsevier)
Coagulation Disorders- Inherited
• Hemophilia A due to deficiency of factor Factor VIII level

VIII Less than 2 units/dL Severe: frequent spontaneous bleeds
into joints and muscles
• X-linked disorder seen in 30-100 per
2-5 units/dL Moderate: some spontaneous
million boys bleeds, bleeding after minor trauma
• May run in families or result from a new 5-45 units/dL Mild: bleeding only after significant
trauma or surgery
mutation
• Untreated, there are bleeds in joints and

muscle
• Factor VIII infusions can prevent this and

are now often used prophylactically
• Hemophilia B is due to deficiency for factor

IX
Noufissa Benajiba et.al., Hémarthrose du genou gauche chez un enfant hémophile de 6 ans,
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232198/figure/F0001/, CC BY 2.0, no changes
Coagulation Disorders- Inherited
• Von Willebrand Disease
• Due to deficiency or inactivity of vWF
• Prevalence of 1 in 10,000
• vWF is involved in adhesion of platelets to

endothelium and carriage of factor VIII
Martin R. Howard & Peter J Hamilton, Haematology, 4th Edition, 2013, p. 74, Fig. 37.2, Fig. 37.3, Churchill Livingstone (Elsevier)
Coagulation Deficiency - Acquired
• Disseminated Intravascular Coagulation

• Excessive coagulation leads to depletion of
coagulation factors
• Vitamin K deficiency: in the newborn or

liver disease
• Vitamin K needed for activation of several

clotting factors
• Acquired hemophilia
• Due to antibodies to factor VIII
Valirie Ndip Agbor et.al., Symmetric affection with ulceration and gangrene of the toes,
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5175299/figure/Fig2/, CC BY 4.0, no changes
Question
Which ONE diagnosis is the most likely in this case?
A 24 year old woman is noticed to be bleeding from a venepuncture site during a difficult
childbirth. Full blood count shows the platelet count has fallen from normal to 30 over 6
hours
Immune thrombocytopenic
purpura
Disseminated intravascular
coagulation
Acquired hemophilia

Summary
 Hemostasis depends on the interaction of the blood vessel, platelets

and coagulation factors
 Vessel and platelet disorders leads to bleeding into skin and mucous
membranes.
 Immune thrombocytopenia is the most common cause
 Hemophilia is the most important inherited coagulation disorder and

can now be managed by prophylactic factor VIII

List of References
• Gargani, Horton-Szar, Shiach, Helbert: Crash Course Haematology and Immunology,

Elsevir 2012

This document is a property of: Hemnath Chan
Note: This document is copyright protected. It may not be copied, reproduced, used, or
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Bleeding Disorders

With Prof. Paul Moss

Hemnath Chan, hemnath5393@gmail.com

 Hemostasis is dependent on a combined response to injury from the

 A range of inherited and acquired disorders can lead to bleeding

 Vessel and platelet problems lead to purpura and bruising whereas

Hemnath Chan, hemnath5393@gmail.com

• After injury the vessel can vasoconstrict to

• Platelets attach to the exposed collagen

• They then undergo platelet adherence and

• Coagulation factors ensure that thrombin

Hemnath Chan, hemnath5393@gmail.com

• Platelets are shed from the cytoplasm of

• They are 3x 0.5 microns and contain dense

• The major regulator of platelet production

• Their main function is to form a plug in the

• The platelets demonstrate

Hemnath Chan, hemnath5393@gmail.com

• Adhesion occurs when von Willebrand

• This exposes GPIIb/IIIa which binds to vWF

• Platelet activation leads to release of

Fig. 6.2 Platelet adhesion reactions. Von factor (vWF) binds

• This is a biological amplification system

• This culminates in the generation of

• This converts soluble fibrinogen into fibrin

• Fibrin enmeshes the platelet aggregates

Hemnath Chan, hemnath5393@gmail.com

• Full blood count

• Activated partial thromboplastin time

• Measures factors VIII, IX, XI and XII

• Normal clotting time is 30-40 seconds

Hemnath Chan, hemnath5393@gmail.com

• Prothrombin time (PT)

• Measures factors VII, X, V, prothrombin and Test Proloned Proloned Low

Hemnath Chan, hemnath5393@gmail.com

The nuclei are extruded

GP1b binds to VWF to

They adhere to each other

Hemnath Chan, hemnath5393@gmail.com

• Hereditary hemorrhagic telangiectasia

• AD inheritance, mutations in endoglin

• telangiectasia develop in skin, mucous

• Immune mediated thrombocytopenia

• Ig G antibodies against platelets

• Treat: steroids, splenectomy or

• Infection, Pregnancy, Drugs

• Thrombotic thrombocytopenic purpura

• Bone marrow failure

• Deficiency of ADAMTS13 metalloprotease

• Treat with plasma exchange

• Hemophilia A due to deficiency of factor Factor VIII level

• Untreated, there are bleeds in joints and

• Factor VIII infusions can prevent this and

• Hemophilia B is due to deficiency for factor

• Von Willebrand Disease

• Due to deficiency or inactivity of vWF

• vWF is involved in adhesion of platelets to

• Disseminated Intravascular Coagulation

• Vitamin K deficiency: in the newborn or

• Vitamin K needed for activation of several

• Due to antibodies to factor VIII

Hemnath Chan, hemnath5393@gmail.com

 Hemostasis depends on the interaction of the blood vessel, platelets