Chapter 25

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chapter notes for essential hematology

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Chapter 25
Bleeding disorders caused by vascular and platelet
abnormalities
Abnormal bleeding/bleedings disorders are caused by vascular disorder, thrombocytopenia,
defective platelet or coagulation process.
How to quickly identify the cause?


Vascular and platelet disorders are associated with bleeding from the mucous membranes
and into the skin



Coagulation disorders are associated with bleeding from joints or soft tissue

What are some clinical differences between platelet/vessel wall diseases and coagulation
diseases?


Mucosal bleeding and petechiae are common in plt/vessel wall disesease but rare in
coagulation.



Deep hematomas are rare in plt/vessel wall disease but seen as a characteristic feature in
coagulation disorders.



Bleeding from skin cuts tend to be persistent in plt/veseel wall disease but at minial in
coagulation



Lastly the prevalence due to sex is equal in plt/vessel but predominat (80%) male in
coagulation disease

Vascular Bleeding Disorders


VBDs are characterized by easy bruising and spontaneous bleeding from small vessels.
Bleeding is mainly in the skin causing petechial or ecchymoses.



Abnormality is localized to the vessels or in the perivascular CT

Hereditary VBDs
1. Herediatary Hemorrhagic Telangiectasia


Uncommon; autosomal dominant



Underlying genetic defects such as of the endothelial protein endoglin



Telangiectasia (dilated microvascular swellings) develop in the skin, mucous
membranes and internal organs during childhood, becoming more pronounced in
adulthood.



Recurrent epistaxis (nose bleeds) and GI bleeding also occur

2. Connective Tissue (CT) Disorders (Ehlers-Danlos Syndrome and PXE)


EDS is characterized by collagen abnormalities with purpura as a result of
defective platelet aggregation, hyper-extensibility of joints and hyper-elastic
friable (breaks easily) skin



PXE called pseuoxanthoma Elasticum is characterized by the degeneration of
elastic fibres. PXE is associated with arterial haemorrhage and thrombosis.

3. Giant Cavernous Hemangioma


This is a congenital malformation that causes chronic activation of coagulation

Acquired Vascular Defects
1. These include diseases like Henoch-Schnlein Syndrome, seen in children and often
follow an acute upper respiratory infection. HSS is characterized by a rashn itching and
painful joint swelling. Cases show severe purpura on legs with bullous formation or early
urticarial lesions.
2. Purpura associated with infection or caused by atrophy (senile) of cutaneous support
tissues
3. Scurvy as a result of Vit C deficiency; causes defective collagen which leads to
perifollicular petechiae, bruising or mucosal bleeds

4. Steroid purpura associated with long term steroid use or Cushings Syndrome; caused by
defective vascular supportive tissue

Thrombocytopenia


Abnormal plt function is characterized by spontaneous skin purpura, mucosal
bleeding and prolonged bleeding after trauma.

1. Failure of platelet production is the most common cause of thrombocytopenia ; assoc.
with BM failure. Congenital form is rare and occurs as a result of mutation of the c-MPL
thrombopoietin receptor.
2. Increased destruction of plts is caused by Autoimmune (idiopathic) thrombocytopenic
purpura (ITP)
ITP is divided into chronic and acute forms
Chronic ITP


High incidence in women 15-50 yrs and most common cause of thrombocytopenia
without anaemia or neutropenia



Usually idiopathic but can be seen in assoc. with SLE (systemic lupus erythematous),
Helicobacter pylori, CLL or Hodgkin’s.

Pathogenesis: IgG (plt autoimmune antibody) is directed against antigen sites on the GP IIb/IIa
or Ib complex.
Clinical Features: insidious onset with petechial bleeding, easy bruising and menorrhagia. In
severe cases, mucosal bleeding (epistaxis or gums) occur.
Diagnosis: low plt count (10-100x 10^9/L); normal or increased megakaryocytes; sensitive tests
demonstrate anti-GP GP IIb/IIIa or GPIb antibodies on plts surface or in serum
Treatment with corticosteroids, IV immunoglobulins, Immunosuppressive drugs (Rituximab),
splenectomy, thrombopoietin-receptor agonists, plt transfusions or SCT.

Acute ITP
Most common in children, following after vaccination (75% prevalence) or infection such as
Mono or Chickenpox.
Diagnosis is one of exclusion.
3. Infections such as viral/protozoal may cause thrombocytopenia
4. Post transfusion purpura. Antibodies develop against human plt antigen-1a (HPA-1a)
5. Drug-induced immune thrombocytopenia. Quninine, quinidine and heparin
6. Thombotic thrombocytopenic purpura (TTP) and haemolytic uraemic syndrome
(HUS)


Characterized by microvascular thrombosis, cell fragmentation and
mircoangiopathic HA


In TTP there is a

defeiciency in ADAMTS13
metalloprotease which breaks down
VWF. In adults neurological
changes and liver dysfunction
occur. Congenital TTP is due to
mutated ADAMTS13 (lack of
synthesis) and acquired is due to
autoantibody IgG which leads to
multimetric VWF complexes
(strings) in plasma (forms occlusive
plt thrombi).


In HUS ADAMTS13

levels are normal. In children organ
damage is caused to the kidneys.
HUS follows infection with E.Coli

7. Disseminated Intravascular Coagulation. Increased rate of plt destruction through
consumption of plts because of their role in DIC??
8. Increased Splenic pooling where up to 90% of plts are sequestered in the spleen
(splenomegaly). Not associated with bleeding
9. Massive transfusion syndrome. Massive amount of stored blood when transfused show
abnormal clotting and thrombocytopenia

Disorders of Platelet function
Suspected in patients who show skin and mucosal bleeding. Plt count and VWF are normal!
Diagnosis: prolonged BT or PFA-100 test (assoc with aspirin therapy or uremia in acquired)
For hereditary, in vivo tests on plt aggregation and plt nucleotide levels are done.
Divided into hereditary and acquired. Inherited produce defects of the different phases of plt
reactions.
Hereditary
1. Thrombasthenia (Glanzmann’s disease)
Deficiency in membrane GP IIb/IIIa. These GPs form the VWF and fibrinogen receptors.
Disease thus leads to failure of primary plt aggregation
Autosomal recessive inheritance
2. Bernard Soulier Syndrome
Deficiency in GPIb; plts are larger than normal. Adhesion is defective! Cannot to VWF nor
exposed subendothelial CT. No plt aggregation with ristocetin.
3. Storage Pool diseases
Absence of alpha granules and deficiency in their proteins; plts larger than normal

Acquired
1. Antiplatelet drugs
Aspirin therapy is the most common cause of defective plt function. Aspirin inhibits
cyclooxygenase which impairs thromboxane A2 synthesis.
Effects? No release rxn and aggregation with arachidonic acid, collagen, adrenaline or ADP
It produces abnormal PFA-100. Assoc. with GI bleeding
2. Hyperglobineamia
Assoc. with myeloma or Waldenstrom disease; impairs plt adhesion, release and aggregation
3. Uremia
Heparin, dextrans, alchol and radiographic agents cause defective plt function
4. Myeloproliferative and myelodysplastic disorders
Intrinsic abnormalities of plt function

Thrombomimetics
Drugs that increase plt production by activating the thrombopoietin receptor on megakaryocytes.
Eg. Thromboplastin, eltrombopag
Effect? Disturbed liver function and increased BM reticulin; long term use causes marrow
fibrosis (reverts when drug is stopped)

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