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)