QUALITATIVE Disorders of

Platelets and vasculature

3. Qualitative disorders of platelets and vasculature
Learning Objectives

At the end of this unit of study, the student

should be able to:
1. Define and differentiate among petechiae, purpura,
ecchymosis, hematoma, and easy bruisability.
3. Identify laboratory tests that can be ordered to
screen for abnormalities of the hemostatic system.
4. Explain the expected clinical consequences when a
patient has an abnormality of platelets or blood
vessels.
5. Correlate quantitative variations in the platelet
count with disease manifestations
Learning Objectives

6. Discuss the mechanism of the platelet defects

associated with myeloproliferative diseases, uremia,
and liver disease.
7. Explain the effect of aspirin and its duration on platelet
function.
8. Discuss the mechanisms of the action of antiplatelet
drugs.
9. Describe the defect in each of the following hereditary
disorders storage pool disease, gray platelet syndrome,
Glanzmann thrombasthenia, and Bernard-Soulier
syndrome.
Learning Objectives

10. Compare and contrast Glanzmann thombasthenia and

Bernard-Soulier syndrome.
11. Discuss and identify conditions associated with
acquired vascular disorders.
Copyright © 2016, 2015, 2012 by Saunders, an
5
imprint of Elsevier Inc.

Chapter Overview
 Qualitative platelet disorders
 Disorders of platelet aggregation
 Disorders of platelet adhesion
 Inherited giant platelet syndromes
 Disorders of platelet secretion
 Inherited disorders of other receptors and signaling pathways
 Acquired defects of platelet function
 Vascular disorders
 Hereditary disorders
 Acquired disorders
Approach to the Bleeding
Patient
 Clinical Assessment
 Is a bleeding tendency present?
 Is the condition familial or acquired?
 Is the disorder one affecting
 Primary hemostasis (platelet or vessel wall dependent)
 Fibrin formation and stability (dependent on the fluid phase of coagulation)
 Is there another disorder present that could be the cause of or might
exacerbate any bleeding tendency?
Is a Bleeding Disorder Present

 Consider
 Presenting complaint
 Medical, family and drug histories
 Principal Presentations
 Easy bruising
 Spontaneous bleeding from mucous membranes
 Menorrhagia
 Excessive bleeding after trauma
 Especially surgery or parturition
Easy Bruising

 Common manifestation in disorders of primary hemostasis

 Size of lesion may indicate significant disease
 Petechiae (<3 mm)
 Intermediate purpura (3 mm-1 cm)
 Ecchymoses (>1 cm)
Easy Bruising

 Common manifestation in disorders of primary hemostasis

 Presence on trunk without recognized trauma more significant than on limbs
in absence of trauma
 Patients may also report excessive and prolonged bleeding from cuts
FIGURE 31-1 Schematic drawing of bleeding manifestations in intact skin. a. Petechiae. b. Ecchymosis. c.
Hematoma.
 Mucosal Bleeding & Menorrhagia

 Epistaxis –nose bleed

 History, recurrence
 Gingival bleeding
 Spontaneous
 Chronic/good dental hygiene
 Hematuria,
 Hemoptysis-coughing up blood
 Hematemesis-vomiting blood
 The three H’s are relatively uncommon presenting features
 Menorrhagia
 Common manifestation of bleeding disorders
 Surgical Hemorrhage

 Unexpected bleeding after

 Trauma, especially surgical trauma
 Normal hemostasis
 After surgery or accidental trauma
 Hemostatic mechanisms intact at that time
 Dental extraction, tonsillectomy
 Significant challenge to hemostasis
 Delayed wound healing
 Postpartum hemorrhage
Joint and Muscle Bleeds

 Hemarthrosis and spontaneous muscle hematomas

 Characteristic of severe plasma protein deficiencies

Hemophilias
 Rarely occur in other bleeding disorders
 Except severe von Willebrand disease

 Joint bleeds (Hemoarthrosis)

 Pain, swelling, rarely discoloration
 Familial or Acquired

 Consider
 Age at presentation
 Duration and type of symptoms
 Response to previous hemostatic challenges
 Family history
 Complete drug history
 Exposure to toxins
 Presence of other diseases
 Potential diagnostic difficulties – mild VWD
 Family history
 May be informative
 May also be misleading
 1/3 of cases of hemophilia due to new mutations
Type of Bleeding Disorder

 Disorder of
 Primary hemostasis
 Fibrin formation
 Premature clot dissolution
 Spontaneous skin petechiae
 Usually severe thrombocytopenia
 Spontaneous hemarthrosis
 Usually coagulation factor deficiency
Type of Bleeding Disorder

 Quantitative & Qualatative platelet disorders

 Mucosal bleeding and bruising
 VWD
 Combination of primary hemostatic failure & impaired fibrin formation
 Timing of bleeding in relation to trauma may be informative
Lab Evaluation of
Abnormal Bleeding
 Laboratory tests of coagulation and hemostasis
 Should not be a substitute for clinical assessment
 Screening tests
 Unhelpful in the prediction of bleeding risk
 Should not be part of routine preoperative assessment
 Exception – preoperative assessment in infants and young children
 Should be followed by more specific studies
Typical Screening Test Profile

 Prothrombin Time (PT)

 Activated Partial Thromboplastin Time (APTT)
 Quantitative platelet count
 (+/-) Bleeding Time Test (BTT)
 (+/-) Thrombin Time
Platelet Disorders
 Platelet Disorders

 Quantitative-Next lecture
 Thrombocytopenia
 Thrombocytosis
 Qualitative
 Morphologic abnormalities
 Macrothrombocytes
 Microthrombocytes
 Hypogranular or agranular platelets
Types of Bleeding in Disorders
of Primary Hemostasis
Qualitative (Functional)
Platelet Disorders
Qualitative Platelet Disorders

 Clinical symptoms vary

 Asymptomatic → mild, easy bruisability → severe, life-threatening
hemorrhaging
 Type of bleeding
 Petechiae
 Easy & spontaneous bruising
 Bleeding from mucous membranes
 Prolonged bleeding from trauma
Qualitative Platelet Disorders

 Laboratory screening tests results

 Similar to those found in thrombocytopenia
 Platelet count usually normal
 If mildly ↓ plt ct, BT prolonged more than expected for degree of thrombocytopenia
FIGURE 31-2 a. Large granular platelet. b. Increased numbers of platelets, some of which have normal morphology,
some of which are hypogranular or agranular, and one giant agranular platelet. (Note: The central nucleated cell [arrow]
is a micromegakaryocyte.) (Peripheral blood, Wright-Giemsa stain, 1000X magnification)
Inherited Disorders
of Platelet Function
 Inherited Qualitative
Platelet Disorders-Disorders of Aggregation
 Defects in platelet-platelet interaction
 Glanzmann's thrombasthenia
 Deficiency or defect in GPIIb/IIIa

 Congenital afibrinogenemia
 Deficiency of plasma fibrinogen
 Acquired Qualitative
Platelet Disorders-Disorders of Aggregation

 Acquired vWillebrand disease

 Acquired uremia
 Glanzmann’s Thrombasthenia
(GT)
 Diagnostic Criteria
 AR trait
 No significant bleeding symptoms in heterozygotes
 Bleeding symptoms (homozygotes)
 Purpura, epistaxis, gingival bleeding, menorrhagia, gastrointestinal bleeding and hematuria

 Bleeding severity
 Ranges from mild bruising to severe, recurrent mucocutaneous bleeding beginning at birth
occasionally with bleeding after circumcision.
 Glanzmann’s Thrombasthenia

 Laboratory evaluation
 Normal platelet count & morphology
 Decreased GPIIb/IIIa by flow cytometry
 Prolonged BT
 Absent or severely diminished
 Platelet aggregation in response to ADP, collagen, thrombin, & epinephrine
 Normal agglutination by ristocetin & VWF
 Platelet Factor 3 levels diminished
 Decreased platelet fibrinogen in α-granules
 Absent receptor-mediated endocytosis
Glanzmann’s Thrombasthenia
 Molecular genetics
 >70 different molecular defects of either gene GPIIb or IIIa
 ITGA2B and ITGB3 on chromosomes17
 Codes for GP IIb/IIIa
 GT Type I
 Undetectable or trace amounts (<5%) of GP-IIb/IIIa
 Absent or severely diminished
 Fibrinogen content, fibrinogen binding, clot retraction
 GT Type II
 GPIIb/IIIa of up to 15% of normal
 Platelet α-granule fibrinogen of 30-60% of normal

 Variant GT (Type III)

 Qualitative defects of GPIIb/IIIa
 Laboratory diagnostic features of GT except GPIIb/IIIa levels of 50-100% of normal
 Glanzmann’s Thrombasthenia

 Differential diagnosis
 Afibrinogenemia/severe hypofibrinogenemia
 Platelet studies comparable
 Coagulation tests are abnormal

 Acquired autoantibodies to GPIIb/IIIa

 Inhibit fibrinogen receptor function
Glanzmann’s Thrombasthenia

 Treatment
 Transfusion of normal platelets
 Prevention of alloimmune reactions necessary for patients
with frequent transfusions.
 Use pre-storage, leukocyte-reduced apheresis platelets or HLA-
matched donor platelets.

 Recombinant VIIa (rVII-NOVO 7)

 Used in surgical and non-surgical bleeding for patients
refractory to platelet transfusion
 Though to enhance burst of thrombin generation.
 Inherited Qualitative
Platelet Disorders-Disorders of Adhesion

 Defects in platelet-vessel wall interaction

 Bernard-Soulier syndrome
 Deficiency or defect in GPIb/IX/V

 Defects in collagen receptors

 GP-IcIIa; GPVI

 von Willebrand disease

 Deficiency or defect in plasma VWF
Bernard-Soulier Syndrome
(BSS)-Giant Platelets
 Diagnostic criteria
 AR trait
 No significant bleeding symptoms in heterozygotes
 Bleeding symptoms (homozygotes)
 Purpura, epistaxis, gingival bleeding, and menorrhagia, without hemarthrosis, deep visceral
hematomas

 Bleeding severity ranges from mild bruising to severe, recurrent mucocutaneous

bleeding
 Bernard-Soulier Syndrome

 Laboratory evaluation
 Moderate to severe thrombocytopenia
 Large platelets with a heterogeneous size distribution on PB smear
 Prolonged BT
 Normal platelet aggregation in response to ADP, collagen, arachidonic acid, and
epinephrine
 Absent platelet agglutination by ristocetin and VWF (not corrected by normal
plasma)
 Decreased GPIb/IX/V by flow cytometry
 Results in inability of BSS platelets to bind to vWF.
FIGURE 31-7 Platelet morphology in Bernard-Soulier syndrome. (Peripheral blood, Wright-Giemsa stain, 1000X
magnification)
Bernard-Soulier Syndrome

 Molecular genetics
 Deficiency or dysfunction of GPIb (GPIb or GPIb) or GP-IX
 >600 mutations identified
 Most frequent mutations involve defects in GPIa
 Necessary for normal function
 Contains binding sites for vWF and thrombin

 Defects involving GPIb and GPIX may also result in BBS

 Variant forms have been identified

Bernard-Soulier Syndrome

 Treatment
 Platelet transfusions
 Common concerns for alloimmunization are the same as in GT
 Bernard-Soulier Syndrome
 Differential diagnosis
 Other congenital thrombocytopenia's and diseases associated with giant
platelets
 May-Hegglin anomaly
 Large platelets, variable thrombocytopenia

 Dohle body-like neutrophil inclusions

 Platelet function & platelet membrane GPs are N

 Problem is abnormal microtubule distribution and Epstein syndrome

 Acquired autoantibodies to GPIb

 VWD
 Platelet agglutination by ristocetin corrected by normal plasma

 Flow cytometry of platelet GPs is normal

 Inherited Qualitative Platelet Disorders
Disorders of Platelet Secretion

 Defects of platelet secretion and signal transduction

 Diverse group of disorders impaired secretion of granule contents
 Abnormal aggregation during platelet activation
 Abnormal platelet function due to
 Granules or their contents are diminished (storage pool deficiency)

 Aberrations in the activation mechanisms governing secretion and other responses

Copyright © 2016, 2015, 2012 by Saunders, an
44
imprint of Elsevier Inc.

Qualitative Platelet Disorders

 Inherited giant platelet syndromes
 Giant platelets with velocardiofacial syndrome
 Giant platelets with abnormal surface glycoproteins and mitral valve
 Familial macrothrombocytopenia with GP IV abnormality
 Montreal platelet syndrome
 Gray platelet syndrome
 May-Hegglin anomaly
 Fechtner syndrome
 Sebastian syndrome
 Hereditary macrothrombocytopenia
 Epstein syndrome
 Mediterranean macrothrombocytopenia
 Inherited Qualitative Platelet
Disorders-
Disorders of Platelet Secretion
 Abnormalities of platelet granules
 Storage pool deficiency
 αSPD
 δSPD
 αδSPD

Quebec platelet disorder

Thromboxane pathway disorders
δ-Storage Pool Disease

 Deficiency of platelet dense granules

 Mild → moderate bleeding
 Not typically serious
 May be limited to easy brusing
 Prolonged BT
 Platelet aggregation
 Second wave of aggregation with ADP & EPI absent or blunted
 Collagen response markedly ↓
 Electron microscopy – dense granules decreased
 Ratio of total platelet ATP:ADP ↑ (>2.5)
 δ-Storage Pool Disease
 Associated with other disorders
 Chediak-Higashi syndrome-Rare disorder
 Partial oculocutaneous albinism, frequent pyogenic infection, giant lysosomal
granules in cells with dense granule deficiency and hemorrhage.
 Hermansky-Pudlak syndrome
 Tyrosinase-positive oculocutaneous albinism, defective lysosomal function
 Wiskott-Aldrich syndrome
 TAR (thrombocytopenia, absent radii) syndrome
 Multiple etiologies
 Lack of organelle development in MKs
 Impaired localization of the nucleotides to DG
 α-Storage Pool Disease

 Deficiencies in platelet α-granules

 Gray Platelet Syndrome (GPS)
 Gray appearance of platelets with absence of granules on PB smears
 AR disorder with lifelong bleeding diathesis
 Mild thrombocytopenia with prolonged BT
 EM – absent or markedly decreased α-granules
Gray Platelet Syndrome
 α-Storage Pool Disease
 Deficiencies in proteins typically stored in platelet α-granules
 VWF, TSP, FN, F-V, HK, PDGF

 Platelet aggregation responses generally normal

 Molecular level
 Mutations in NBEAL2
 Believed to be involved in vesicular trafficking and αG development

 Treatment
 Platelet transfusions for bleeding
 Cryoprecipitate to control bleeding
 Desmopressin acetate
 Prophylaxis for dental procedure
 Quebec Platelet Disorder

 Abnormal proteolysis of α-granule proteins

 Resulting from increased levels of Platelet Urinary-type plasminogen activator
(uPA)
 AD disorder
 α-granule structure preserved
 Platelets morphologically normal (light microscopy)
 Platelets moderately decreased
 Variable bleeding history
 Mucocutaneous bleeding
 Disorders of Platelet
Secretion
Thromboxane pathway disorders
 Aspirin-like effects
 Hereditary deficiencies
 Ultrastructure and granular contents are normal
 Enzyme deficiencies
 Cyclooxygenase
 Thromboxane synthase
 Thromboxane receptors

 Pathway mechanism-pathway initiating cascade of events

 Resulting in secretion and aggregation of platelets
 Figure 10-12, p 150
 Role of aspirin and ibuprofen
 Inhibits cyclooxygenase
 Abnormalities in
Arachidonic Acid Pathway
 Cyclooxygenase deficiency
 Mild bleeding disorder
 Impaired aggregation response
 ADP, EPI, collagen, AA

 Impaired endothelial cell PGI2 production

 Thromboxane synthase deficiency

 Mild bleeding disorder
 Same platelet aggregation abnormalities
 No effect on PGI2 production
 Inherited Qualitative
Platelet Disorders
 Signal transduction defects
 Primary secretion defects
 Defect in platelet-agonist interaction
 Receptor defects: TXA2, collagen, ADP, epinephrine, serotonin
 Defects in G-protein activation
 Defects in phosphatidylinositol metabolism
 Defects in protein phosphorylation
 Defects in arachidonic acid pathways & TXA2 synthesis
 Defects in calcium mobilization
 Inherited Qualitative
Platelet Disorders- Receptors and Signaling
Bleeding
Pathways
 Abnormalities in the platelet secretory mechanism

 Typically mild → moderate bleeding

 Mucocutaneous

 Easy bruising, menorrhagia, excessive post operative and

post partum
 Patients usually have prolonged BT
 Absence of second wave of platelet aggregation with ADP or Epi, and ↓ aggregation
with collagen

 Must be differentiated from

 Acquired abnormalities of platelet secretion induced by drugs such as aspirin

 Certain systemic diseases

 Defect in Platelet-
Receptors
Impaired platelet and Signaling Pathways
responses
 Single agonist in platelet aggregation assays
Agonist Interaction
Abnormality
 is usually at the level of the platelet surface receptor for a specific
agonist
 Documented receptor defects include
 TXA2 (TPa)
 ADP (P2Y12)
 EPI
 Serotonin
 Collagen (GPIa/IIa or GP-VI)
 57

Inherited Disorders of Other

Receptors and Signaling Pathways
 Collagen receptors
 Glycoprotein (GP) Ia/IIa integrin deficiency
 Clinical features
 Lifelong mild bleeding disorder

 Laboratory features
 Lacks aggregation response to collagen

 Platelets do not adhere to collagen

 Glycoprotein VI (GPVI) deficiencies

 Clinical features
 Mild bleeding

 Laboratory features
 No aggregation to collagen

 Adhesion to collagen impaired

Copyright © 2016, 2015, 2012 by Saunders, an
58
imprint of Elsevier Inc.

Inherited Disorders of Other

Receptors and Signaling Pathways
 ADP receptors
(Cont.)
 Three receptors

 ADP, P2X
 Linked to ion channel that facilitates calcium ion influx

 P2Y1 and P2Y12

 G-protein linked receptors

 Clinical features
 Mild bleeding tendencies

 Laboratory features
 P2Y12 deficiency
 Decreased platelet aggregation in response to ADP
Copyright © 2016, 2015, 2012 by Saunders, an
59
imprint of Elsevier Inc.

Inherited Disorders of Other Receptors

and Signaling Pathways (Cont.)
 Epinephrine receptors
 Clinical features
 Laboratory features
 Decreased platelet activation
 Decreased aggregation in response to epinephrine

 Calcium mobilization defects

 Features
 Insufficient release of calcium from dense tubular system
 Cytoplasmic ionic calcium never reached levels high enough to support secretion
 Result from abnormal G protein subunits and phospholipase C isoenzymes.
Copyright © 2016, 2015, 2012 by Saunders, an
60
imprint of Elsevier Inc.

Inherited Disorders of Other Receptors

and Signaling Pathways (Cont.)

 Scott syndrome
 Inheritance
 Features of syndrome
 Bleeding disorder

 Stormorken syndrome
 Features of syndrome
 Mild bleeding tendency due to platelet dysfunction, thrombocytopenia, anemia
functional asplenia and other constitutive disorders.
Scott Syndrome

 Rare AR disorder
 Abnormal
 Calcium-induced phospholipid scrambling
 Phospholipid “flip”
 Lack of generation of thrombin on platelets
 Activated Scott platelets
 Secrete and aggregate normally
 Fail to transport Phosphatidylserine from the inner to the outer
Phosphatidylethanolamine leaflet of the membrane
 Result
 Vitamin-K-dependent factors fail to bind
 Tenase & prothrombinase complexes fail to form
 Platelet plug formation normal
 No fibrin plug or stabilization
Arachidonic Acid Pathways
& TXA2 Synthesis
 Abnormalities
 Impaired liberation of arachidonic acid
 Cyclooxygenase deficiency
 Thromboxane synthase deficiency
Abnormalities in
Arachidonic Acid Pathway
 Important positive feedback loop ↑ platelet activation
 Liberation of AA from PLs and conversion to TXA2
 Defects in the liberation of AA
 Defects of PL-A2
Laboratory Test Results in Selected Platelet Disorders
FIGURE 31-6 Ultrastructural components associated with inherited disorders of platelet function.
FIGURE 31-8 Platelet aggregation patterns in disorders of platelet function. a. Bernard-Soulier syndrome. b. von
Willebrand disease. c. Glanzmann’s thrombasthenia. d. δ-storage pool disease, aspirin ingestion, uremia, thromboxane
A2 deficiency. e. Myeloproliferative disease.
Acquired Disorders of Platelet
Function
 Bleeding less severe than seen in BSS and GT
 Much more common than inherited disorders
 Seen in
 Setting of trauma or surgery
 Presence of additional hemostatic defects

 Detected by abnormal platelet function test

 BT, plt aggregation

 Defects quantified by laboratory tests do not correlate precisely with risk for
bleeding
Copyright © 2016, 2015, 2012 by Saunders, an
68
imprint of Elsevier Inc.

Acquired Defects of Platelet

Function
 Drug-induced defects
 Inhibitors of prostaglandin pathway
 Action of aspirin
 Other drugs
 Alcohol consumption
Drugs that Alter Platelet
Function
 Variety of drugs alter platelet function
 Some used specifically for their antithrombotic activity
 Others, abnormal platelet function unwanted side effect
 Effect on platelet function
 Defined by an abnormality of BT or platelet aggregation
 Aspirin is only one with definitely established risk of excessive bleeding
Drugs that Alter Platelet
Function
 Aspirin
 Impairs
 Acetylation & irreversible inhibition of platelet cyclooxygenase (COX-1 inhibitor)
 Effects last entire circulating life span (~9-10 days)

 Acetylates cyclooxygenase in ECs

 Blocking synthesis of PGI2
 ECs can recover CO activity by resynthesizing new enzyme
 Drugs that Alter Platelet
Function
 Aspirin
 Platelet aggregation
 Primary wave with ADP and EPI
 No secondary wave
 No aggregation with collagen
 Normal with ristocetin
Copyright © 2016, 2015, 2012 by Saunders, an
72
imprint of Elsevier Inc.

Acquired Defects of
Platelet Function (Cont.)
 Drug-induced defects
 Inhibitors of membrane function
 Thienopyridine derivatives
 GP IIb/IIIa receptor inhibitors
 Dipyridamole
 Antibiotics
 Dextrans
 Hydroxyethyl starch
 Miscellaneous drugs
Hematologic Disorders that
Affect

Platelet Function
Chronic Myeloproliferative Disorders
 PV, ET, CIMF
 BM hypercellularity
 Atypical MK hyperplasia
 Clonal disorder of HSC
 Can see either bleeding or thrombosis
 Usually abnormal platelet function
Hematologic Disorders that
Affect Platelet Function
 Leukemias & Myelodysplastic Syndromes
 Bleeding usually due to thrombocytopenia
 Occasionally abnormalities of platelet function
 Dysproteinemias
 MM and Waldenstrom’s macroglobulinemia
 Thrombocytopenia most likely cause of bleeding
Hematologic Disorders that
Affect Platelet Function
 Dysproteinemias
 Walenström macroglobinemia
 Multiple myeloma
 Abnormalities of plt function
 Correlates with concentration of plasma paraprotein

 Hyperviscosity syndrome
 Paraprotein can interfere with fibrin polymerization
Copyright © 2016, 2015, 2012 by Saunders, an
76
imprint of Elsevier Inc.

Acquired Defects of
Platelet Function (Cont.)
 Disorders
 Cardiopulmonary bypass surgery
 Clinical features
 Laboratory features

 Liver disease
 Clinical features
 Laboratory features

 Uremia
 Clinical features
 Laboratory features
Systemic Conditions

 Cardiopulmonary Bypass Surgery

 Thrombocytopenia
 Abnormal platelet function
 Correlates with duration of the bypass procedure
 Excessive bleeding is uncommon
 Prolonged BT, abnormal platelet secretion & aggregation tests
 Platelet defect likely due to
 Effects of platelet activation
 Fragmentation in extracorporeal circulation
Systemic Conditions

 Liver Disease
 Variety of hemostatic abnormalities
 Mild to moderate thrombocytopenia and platelet
abnormalities
 Alcoholic cirrhosis
 Due to toxic effects of alcoholic

 Chronic liver disease

 Reduced platelet adhesion, abnormal platelet aggregation,
abnormal phospholipid availability and reduced procoagulant
activity

 Possibly storage pool disorders

Systemic Conditions

 Chronic Renal Failure

 Platelet defects associated with uremic plasma
 Dialysis corrects abnormal test results
 Serious hemorrhagic symptoms have ↓

 Primary hemostatic abnormality

 Defect in platelet function

 Platelet function tests abnormal

 Adhesion, secretion, aggregation
Copyright © 2016, 2015, 2012 by Saunders, an
80
imprint of Elsevier Inc.

Acquired Defects of
Platelet Function (Cont.)
 Disorders
 Hereditary afibrinogenemia
 Incidence->150 families
 Clinical features
 Platelets do not exhibit normal function in the absence or near-absence of fibrinogen.

 Laboratory features
 High incidence of hemorrhagic manifestations

 Hyperaggregable platelets
Systemic Conditions
 Anti-platelet Antibodies
 Ig molecules bind to the platelet surface in several pathologic conditions
 ITP, SLE, platelet alloimmunization
 Result accelerated platelet destruction, thrombocytopenia

 Antiplatelet Abs bind and impair platelet function

 Autoantibodies to GPIIb/IIIa – acquired GT
 Autoantibodies to GPIb/IX/V – acquired BSS
Disorders of the Vascular System
 Primary Vascular Disorders
 Most vascular diseases
 Are not associated with platelet or plasma defects
 Most common symptom
 Abnormal bleeding into or under the skin
 Laboratory tests are used to exclude
 Coagulation or platelet disorders
 Majority of patients
 Hemostatic testing is entirely normal, despite a history or physical examination that
suggests substantial bleeding
Primary Vascular Disorders –
Inherited
 Hemangiomas
 Hereditary Hemorrhagic Telangiectasis (HHT)
 Osler-Weber-Rendu Disease
 Ehlers-Danlos Syndrome
 Osteogenesis Imperfecta
 Pseudoxanthoma Elasticum
 Marfan Syndrome
Primary Vascular Disorders –
Inherited
 Hemangiomas-Thrombocytopenia Syndrome
 AKA -(Kasabach-Merritt Syndrome)
 Composed of tangled masses of dilated thin-walled venules (arteriovenous
malformations)
 Usual causes
 Upregulation of growth-promoting factors and/or inhibition of apoptosis

 Strawberry hemangiomas
 Superficial, located in the skin, occur early in life, often regress by adolescence
 Primary Vascular Disorders –
Inherited
 Hereditary Hemorrhagic Telangiectasis (HHT)
 Osler-Weber-Rendu Disease
 Autosomal Dominant disorder
 Multiple telangiectases of the skin, respiratory & GI tracts

 Focal dilations of postcapillary venules in the dermis, often with AV communications

 Can lead to epitaxis and GI bleeding

 Symptoms worsen with age

 Mutations: endoglin (HHT-1; 9q) and activin A receptor (HHT-2; 12q)

 Primary Vascular Disorders –
Inherited
 Ehlers-Danlos Syndrome
 Characterized by defects in collagen production
 Up to 11 separate types described
 Affect skin, ligaments, joints and blood vessels
 Easy bruisability

 Occasional spontaneous rupture of medium to large arteries

 Reduced production of collagen

 Thin or elastic skin, dystrophic scaring, hyperextensible joints
Primary Vascular Disorders –
Inherited
Osteogenesis Imperfecta
 Genetic mutations
 Lead to defects in type I collagen (COLA 1 & 2)
 Manifest as
 Brittle bones (patchy defective bone matrix)
 Blue sclerae
 Poor dentition
 Thin skin, fragile tendons
 At least 4 types have been described, several leading to early death
Primary Vascular Disorders –
Inherited
 Pseudoxanthoma Elasticum
 Rare disorder (defect in ABCC6 gene)
 Elastic fibers of the skin and media of arteries are defective → degeneration
 Patients have lax skin of the neck, face, and axillae, and telangiectases
 Arterial defects can lead to vascular calcification, myocardial infarction and
stroke
 Primary Vascular Disorders –
Inherited
 Marfan Syndrome
 Results from defect in fibrillin-1 gene (AD trait)
 Fibrillin – protein component of microfibrils
 Key component of extracellular matrix → ↓ strength

 Characterized by
 Long limbs, arachnodactyly, dissecting aneurysm, aortic valve incompetence and
dislocation of the lens
 Some patients bruise easily and can bleed excessively
Characteristics of Inherited Disorders of the Vascular System
Classification of Acquired Disorders of the Vascular System
Copyright © 2016, 2015, 2012 by Saunders, an
95
imprint of Elsevier Inc.

Vascular Disorders (Cont.)

 Acquired disorders
 Allergic purpura
 Paraproteinemia and amyloidosis
 Senile purpura
 Drug-induced vascular purpuras
 Miscellaneous causes of vascular purpura
Copyright © 2016, 2015, 2012 by Saunders, an
96
imprint of Elsevier Inc.

Acquired Vascular Disorders

 Allergic purpura
 Henoch-Schönlein purpura
 Vascular defect
 Incidence
 Clinical features
 Laboratory features
 Treatment
Copyright © 2016, 2015, 2012 by Saunders, an
97
imprint of Elsevier Inc.

Acquired Vascular Disorders

(Cont.)
 Paraproteinemia
 Disease correlation
 Interaction with platelets
 Clinical features
 Laboratory features
 Treatment
Copyright © 2016, 2015, 2012 by Saunders, an
98
imprint of Elsevier Inc.

Acquired Vascular
Disorders (Cont.)
 Amyloidosis
 Definition
 Clinical features
 Laboratory features
 Treatment
Copyright © 2016, 2015, 2012 by Saunders, an
99
imprint of Elsevier Inc.

Acquired Vascular
Disorders (Cont.)
 Senile purpura
 Incidence
 Vascular abnormality
 Clinical features
 Laboratory features
Copyright © 2016, 2015, 2012 by Saunders, an
100
imprint of Elsevier Inc.

Acquired Vascular
Disorders (Cont.)
 Drug-induced vascular purpuras
 Drugs
 Clinical features
 Treatment
Copyright © 2016, 2015, 2012 by Saunders, an
101
imprint of Elsevier Inc.

Acquired Vascular
Disorders (Cont.)
 Miscellaneous causes of vascular purpura
 Dietary insufficiency
 Cause unknown
 Psychosomatic