NORMAL HEMOSTASIS AND COAGULATION

PLATELET FUNCTION
• Role of platelets in the circulation
1. Surveillance of blood vessel continuity
2. Formation of primary hemostatic plug (end product
of primary hemostasis = plug)
3. Surface for coagulation factors to make secondary
hemostatic plug
4. Aid in healing injured tissue

[Vascular injury → Vasoconstriction (small hole in blood

vessel/vascular spasm) → Platelet activation → Platelet plug
formation → Coagulation cascade →
PRIMARY HEMOSTASIS
HEMOSTASIS • refers to the role of blood vessels and platelets in
• Term used to describe the normal functioning of the response to a vascular injury.
circulatory system. • Involves vascular intima and platelets [vascular intima –
• Localized blood stopping innermost portion]
• Components: • Activated by desquamation and small injuries to blood
o Mechanism that allow smooth movement of blood vessels
through the blood vessels • Platelets become activated, adhere to the site of injury,
o Includes the clotting factors involved in repair of secrete the contents of their granules, and aggregate with
damaged blood vessels other platelets to form a platelet plug.
o Chemical compounds that prevent the inappropriate
formation of blood clots.
o Compounds that degrades clots
• 3 categories involved:
o Blood vessels
o Blood platelets:
o Soluble plasma proteins

• VASCULAR INTIMA IN HEMOSTASIS

o Provides the interface between circulating blood and
the body tissues
o Endothelial cells- The innermost lining of blood
vessels. Play essential roles in immune response,
vascular permeability, proliferation, and, of course,
hemostasis
o Layers of the Vessel wall
▪ Tunica intima
▪ Tunica media
[Adhesion platelet → Activates (change morphology from ▪ Tunica externa
discoid become round) → Secrete granules (alpha granules &
dense granules = aid aggregation) → Endothelial wall release
Collagen to attract Coagulation Factors →Fibrin mesh –
stabilized the formation of platelet clump]
• Hemostasis involves the interaction of vasoconstriction,
platelet adhesion and aggregation, and coagulation
enzyme activation to stop bleeding.
• Types:
o Primary Hemostasis - platelet plug formation
o Secondary Hemostasis – activation of coagulation
factors
o Tertiary Hemostasis – antithrombotic control/clot
retraction & repair & fibrinolysis

• Tunica intermedia
o Surrounds the tunica intima

MONTEMOR, DJ 19
 o Smooth muscle - layer of smooth muscle cells that
are under involuntary control and can dilate or
constrict
o Connective tissue – produces collagen fibers whose
elasticity is reduced by hypertension
• Tunica intima
o Endothelium - inner most layer of cells that separate
the remainder of the vessel from the lumen
o Basement membrane thin layer of spongy
connective tissue that secretes elastic collagen
o Antithrombotic property – produces prostacyclin
(platelet inhibitors)
o Nitric oxide – counter acts vasoconstriction
o Tissue Factor Pathway Inhibitor (TFPI) - EC-
produced anticoagulant
o Thrombomodulin – activates protein C
o Heparan Sulfate – anti-thrombin
• Tunica adventitia
o Surrounds the tunica media
o Outermost layer
o Composed of Fibroblast – produces collagen
o Connective tissues produce elastic and non-elastic
collagen fibers STAGES FUNCTION CHARACTERISTICS OTHERS
o Prevents ballooning of vessel with high systolic blood
pressure Adhesion Platelet roll Reversible; seals Glycoprotein GP
o Aneurysm – weaknesses in the tunica adventitia and cling to endothelial gaps, Ib/IX/V
• What keeps the blood flows in a blood vessels thin
nonplatelet some secretion of • Receptor
surfaces growth factors, in found in
and prevents from becoming thrombotic? arterioles VIF is platelet for
o Nitric Oxide necessary for VWF
adhesion
o Prostacyclin binding
o Heparin sulfate - Antithrombin III complex • Deficiency of • Deficiency:
VWF: von Bernard-
o Thrombomodulin - Thrombin complex Willebrand Soulier
o Protein C – inactive free clotting factors (labile= disease. Syndrome/
Factor V & VIII) Giant
o Tissue plasminogen activator – activates fibrinolysis Platelet
Syndrome
to eliminate thrombus present in blood vessel Activation Morphologic and functional changes in platelets
o Tissue factor pathway inhibitor – regulates the Secretion Platelets Irreversible; platelet PLATELET a-
extrinsic pathway discharge plugs form, platelet granules
VASCULAR INTIMA OF THE BLOOD the contents contents are secreted, • B-
of their requires Fibrinogen thromboglob
granules ulin
Platelet secrete
contents during • Factor 1, 5 &
adhesion and 11
aggregation, but most • Protein S,
occurs late in the VWF
platelet activation • Factor 4
process. (heparin
inhibitor) &
PDGF
PLATELET
dense-granules
• ADP, ATP
• Calcium
• Serotonin
Aggregati Platelet Irreversible; occurs GP IIb/III a
on adhere to during aggregation, receptor
each other platelet contents are • allows
secreted, essential to binding of
coagulation fibrinogen,
VWF and
fibronectin
• Deficiency:
Glanzmann
thrombasthe
nia
• PLATELETS
o 2 to 3 mm in diameter on a fixed, stained peripheral SECONDARY HEMOSTASIS
blood film. • Describes the activation of a series of coagulation
o Complex and metabolically active cells that interact proteins in the plasma, mostly serine proteases, to form
with their environment and initiate and control a fibrin clot.
hemostasis • Activated by large injuries to blood vessels and
• PLATELET FUNCTION surrounding tissues
o At the time of an injury, platelets adhere, aggregate, • Involves platelets and coagulation system
and secrete the contents of their granules • The activator, tissue factor, is exposed on cell
o STEPS (Adhesion - Secretion - Aggregation) membranes

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 • COAGULATION PATHWAYS
o Extrinsic pathway
▪ Shorter pathway
▪ Tissue trauma
▪ Measured by PT
o Intrinsic pathway
▪ Longer pathway
▪ Blood trauma or collagen contact
▪ Measured by APTT
o Common pathway
▪ Begins with factor X

• COAGULATION FACTORS
o AKA “procoagulants”
o Are glycoproteins synthesized in the liver,
monocytes, EC’s and megakaryocytes.
o Zymogen - inactive form of enzymes [“a” – activated]
o Cofactor - binds, stabilize and enhance activity of
their respective enzymes

• VITAMIN K- Dependent group [IX, X, VII, II-

(MNEMONIC- 1972)]
• Prothrombin group, named after prothrombin due to
resemblance in structure.
• Vitamin K is a quinone found in green leafy vegetables
and is produced by the intestinal organisms.
• Procoagulants
o Prothrombin (f II)
o f VII
o f IX
o fX
• Regulatory proteins
o Protein C, S & Z
• Vitamin K-dependent procoagulants are essential for the
• CLASSIFICATION & FUNCTION OF assembly of three membrane complexes leading to the
PROCOAGULANTS generation of thrombin
o Serine proteases - are proteolytic enzymes of the • Fibrinogen group/Coagulation group
trypsin family. o Factor I, V, XIII, VIII – labile & consume in clotting;
o Activation occurs when the zymogen is cleaved at only group acts as substrate for the fibrinolytic
one or more specific sites by the action of another enzyme plasmin
protease during the coagulation process. • Contact group
o Procoagulant Cofactors - tissue factor, located on o Factor XII, high-molecular-weight kininogen, and
membranes of fibroblasts and smooth muscle cells, prekallikrein
and soluble plasma factors V, VIII, and HMWK. • Prothrombin group
o Transglutaminase - FACTOR XIII COMPLEX COMPONENTS ACTIVATES
Extrinsic tenase VII a, tissue factor, IX and X
phospholipid and
calcium

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 Intrinsic tenase IX a, VIII a, X
phospholipid, and
calcium
Prothrombinase X a, V a, phospholipid Prothrombin
and calcium

• COAGULATION REGULATORY MECHANISMS

o maintain a complex and delicate balance between
thrombosis and abnormal bleeding
o Inhibitors or natural anticoagulants function to slow
the activation of procoagulants and suppress
thrombin production.
o Ensure coagulation is localized
o Prevent excessive clotting or thrombosis
o Principal regulators:
▪ TFPI
▪ AT/ Antithrombin
▪ APC/ Activated Protein C
▪ ZPI/ Protein Z dependent protease inhibitor

• COAGULATION REGULATORY PROTEINS

o TFPI - Kunitz-type serine protease inhibitor and is the
principal regulator of the tissue factor pathway; not
functional until factor X is activated
o Protein S - cofactor of APC & TFPI
o Protein C - converts thrombin function to an
anticoagulant
o Serpin - neutralizes serine proteases

TERTIARY HEMOSTASIS
• Dissolution of Fibrin Clot
• Dependent on Plasminogen Activation
PROTEINS OF FUNCTION
TERTIARY
HEMOSTASIS
PLASMINOGEN Plasma serine protease, plasmin
digests fibrin/fibrinogen
TPA Serine protease secreted by activated
endothelium, activates plasminogen
UROKI NASE Serine protease secreted by kidney,
activates plasminogen
PAI-1 Secreted by endothelium, inhibits
tissue plasminogen activator
A₂ - Antiplasmin Inhibits plasmin
TAFI Secreted by endothelium, inhibits
tissue plasminogen activator

MONTEMOR, DJ 22
 QUALITATIVE DISORDERS: PLATELETS & VESSEL
o GP Ib/IX complex needs (GP Iba, GP IbB and GP IX)
• BLEEDING o The most frequent forms of BSS involve defects in
o Superficial bleeding - Associated with platelet GP Iba synthesis or expression
defect or vascular disorder o Other inherited giant platelet disorder
▪ Petechiae – bleeding of small blood vessel ▪ Giant platelets with velocardiofacial syndrome
▪ Gingival bleeding ▪ Giant platelet with abnormal surface
▪ Epistaxis glycoproteins and mitral valve insufficiency
o Deep tissue bleeding - Associated with plasma ▪ Familial macrothrombocytopenia with GP IV
clotting factor deficiencies abnormality
▪ Hematoma or hemarthrosis ▪ Montreal platelet syndrome
Coagulation Platelet/Vascular ▪ Giant platelet syndrome
Disorder Disorder ▪ May Hegglin anomaly
Site of bleeding Deep tissue Skin, Mucous ▪ Fechtner syndrome
membranes ▪ Sebastian syndrome
Petechiae Rare Common ▪ Hereditary macrothrombocytopenia
Ecchymosis Large, Deep Small, Superficial ▪ Epstein syndrome
Deep dissecting Common Rare ▪ Mediterranean macrothrombocytopenia
hematomas • Von Willebrand Disease
Superficial Common, Common, small o A bleeding disorder characterized by deficiency or
Ecchymoses large and and multiple dysfunction of von Willebrand factor (vWF)
solitary o VWF
Hemarthrosis Common Rare ▪ Synthesized in the endothelium and
Delayed bleeding Common Rare megakaryocytes
▪ Carrier of factor VIII
Bleeding after Yes No
cuts & scratches ▪ Anchor platelets to subendothelium
▪ Autosomal dominant
Bleeding after Immediate, Delayed 1-2 days,
o Mucocutaneous bleeding (+)
surgery or trauma mild severe

QUALITATIVE PLATELET DISORDER

• A problem with the structure or function of the platelet
• The disorder results in a poor “quality” of clotting
• Common causes include
o Missing or defective proteins on the surface of the
platelet membrane
o A deficiency or abnormality in the platelet granules
or their contents (also known as a “storage pool
disorder”)

o Qualitative deficiency of vWF

▪ Type 2
▪ Type 2A
▪ Type 2B
▪ Type 2M
▪ Type 2N – mutation of vWF that recruit binding
of factor VIII, as factor VIII stabilize by binding
vWF the px. has a short life span & factor VIII
(markley decreased), Autosomal Hemophilia
DISORDERS OF PLATELET AGGREGATION o Quantitative deficiency of vWF
▪ Type 1
• Glanzmann thrombasthenia
▪ Type 3
o Disorders of Platelet Aggregation Affecting GP
Von Willebrand Pathogenetic Mechanisms
Ilb/Illa Function, the most abundant platelet surface
Disease Subtype
receptor.
o Prolonged BT, abnormal in vitro clot retraction and
Type 1 VWD • -65% of index cases have
normal platelet count candidate VWF mutations
o Inherited autosomal recessive disorder • -70% of VWF variants are
o Hemorrhagic manifestations (petechiae, purpura, missense substitutions
menorrhagia, Gl bleeding and hematuria) influencing VWF trafficking,
storage, secretion and
DISORDERS OF PLATELET ADHESION
clearance
• Bernard-Soulier Syndrome • Additional transcription and
o Autosomal recessive, characterized by moderate to splicing VWF mutations
severe thrombocytopenia, giant platelets, and Type 2A VWD • Missense variants in
profuse/spontaneous bleeding D1/D2/D’D3 assemblies, A2 and
o Deficiency or dysfunctional GP Ib V-IX CTCK domains
o Prolonged BT
• Interference with HMW multimer
o Normal aggregation in response to all agonist except
formation, storage and secretion
ristocetin (ristocetin – cofactor w/vWF for plt
• Enhanced ADAMTS13
adhesion)
proteolysis

MONTEMOR, DJ 23
 Type 2B VWD • Missense variants in A1 domain • Hermansky - Pudlak syndrome (HPS)
• Enhanced binding to GPIba o Autosomal Recessive, HPS-1 gene (Chromosome
Type 2M VWD • Missense variants in A1 and A3 10q23)
domains o HPS-1 gene – production and control of
• Reduced binding to GPIba (A1 melanosome, dense granules, lysosomes
domain) or collagen (A3 domain) o Tyrosine (+)
Type 2N VWD • Missense variants in D’D3 o Severe oculocutaneous albinism associated with
assembly photophobia, rotary nystagmus, and loss of visual
• Reduced FVIII binding acuity
o Excess accumulation of ceroid - like material in RE
Type 3 VWD • VWF mutations found in 85-90%
cell
of index cases
o Mild to moderate bleeding diathesis
• VWF deletions, nonsense, splice o Platelet Factor is the major cause of death
site and missense mutations o PT & APTT: Normal
o Type 1 o Normal – Prolonged: bleeding time
▪ Quantitative deficiency of vWF o Platelet Aggregation Standard: planted response in
▪ Autosomal dominant by basic course
▪ Partial deficiency • Chediak-Higashi Syndrome
▪ Normal function o Autosomal Recessive (1q)
o Type 2 o Partial albinism - caused by abnormal large
▪ Qualitative deficiency of vWF melanosomes
▪ Autosomal dominant o Large intracytoplasmic granules in WBC and
▪ Functional deficiency platelets
o Type 3 o Immune dysfunction- poor mobilization of marrow
▪ Quantitative deficiency leukocyte pool, defective chemotaxis and bacterial
▪ Absence of vWF degradation activity
▪ Autosomal recessive o May lead to overwhelming infection or
▪ Undetectable VWF protein function lymphoproliferative disorders
Sub- Defect vWF RCof FVIIII Von Willebrand
type Ag multimers • Wiskott-Aldrich syndrome
1 Partial    Normal o X-linked recessive
quantitative distribution
2A Multimerizati    Decreased high
o Defective WASp- cytoskeletal reorganization
on and intermediate o T cell reduces by age
molecular weight o LOW IgM, cell surface GP reduced
multimers
2B Increased    Decreased high o Inability to mound an IgM response to the capsular
binding of molecular weight polysaccharide of bacteria
high multimers o Recurrent pyogenic infections, eczema and bleeding
molecular
weight caused by thrombocytopenia
multimers to o Gene alterations interfere with migration of WBC to
platelets
2M Decreased Nor  Nor Normal
the inflammation site
binding to mal mal distribution o Abnormal cell morphology & defective cytoskeleton
platelets dependent activation signals
2N Decreased    Normal
binding to distribution
o Abnormal cell to cell adhesion
FVIII o IgA & IgE = elevated
3 Complete    Absent o IgG = normal
deficiency
Platelet Increased    Decreased high o IgM = low
type binding of molecular weight o Decreased aggregation response to ATP,
high multimers epinephrine, & collagen
molecular
weight o Low dense granules
multimers to • TAR syndrome
platelets
*Patients with type 2N are usually compound heterozygotes for a type I mutation
o Autosomal Recessive
and therefore have low vWF Ag and RCof. o Thrombocytopenia (absence or hypoplasia of
Rcof = Ristocetin Cofactor activity: vWF Ag =von Willebrand factor antigen. megakaryocytes) that presents in early infancy with
DISORDERS OF PLATELET SECRETION (RELEASE bilateral radial anomalies.
REACTIONS) o Skeletal abnormalities of the ulna, radius and lower
• STORAGE POOL DISEASE extremities
o Dense granule deficiencies o Thumbs are present
▪ Disorder arises from an inability to package the o Reduced number of platelets = hypomegakaryocytic
dense granule content. thrombocytopenia
▪ Serotonin transport mechanism disorder • Gray Platelet syndrome
▪ Nucleotide transporter MRP4 (ABCC4) gene o Heterogenous disorder associated with
disorder abnormalities in alpha granule formation and
o Alpha granule deficiencies maturation
▪ Alpha granules are storage for proteins o Autosomal recessive
▪ 50-80 alpha granule per platelet, responsible for o Platelet inability to store alpha granule protein
the granular appearance in PBS o Platelets appear gray on PBS
• THROMBOXANE PATHWAY DISORDERS o Mild thrombocytopenia, mild to moderate bleeding
o Aspirin like effects o Splenomegaly and fibrosis
• DENSE GRANULE DEFICIENCIES o Easy bruising, menorrhagia, excessive postpartum
o Hermansky-Pudlak Syndrome or postoperative bleeding
o Chediak-Higashi Syndrome o Platelet: normal with variable morphology
o Wiskott-Aldrich Syndrome o Platelet Aggregation Standard: normal in primary
o Thrombocytopenia- Absent Radius (TAR) Syndrome wave BUT absence in secondary wave when
• ALPHA GRANULE DEFICIENCY simulated with ADP, epinephrine, & arachidonic acid
o Resistin Agglutination: Normal
o Gray Platelet Syndrome

MONTEMOR, DJ 24
• Quebec Platelet defect
o Autosomal dominant
o Delayed bleeding
o Deficiency of alpha granule multimerin leading to
decreased content of platelet Factor V
o Abnormal proteolysis of alpha granule proteins due
to increased levels of platelet urinary type
plasminogen activator
o Normal or Slight thrombocytopenia
o Reduced aggregation with epinephrine
• SUMMARY
o Platelet Adhesion Disorder
▪ Von Willebrand Disease
▪ Bernard Soulier syndrome
o Platelet Aggregation Disorder
▪ Glanzmann thrombasthenia
▪ Congenital afibrinogenemia
o Disorder of Platelet Secretion & Abnormalities of
Granules
▪ Storage pool deficiency
▪ Quebec platelet disorder
o Disorder of Platelet Secretion & Signal
Transduction
▪ Defects in plt-agonist interaction
o Cytoskeletal Regulation Defect
▪ WAS
o Membrane Phospholipid Defect
2. Disorders that affect platelet function
▪ Scott syndrome
o Myeloproliferative Neoplasms
▪ PCV
▪ CML
▪ ET
▪ MMM
o Multiple Myeloma and Waldenstrom
Macroglobulinemia – results from putting platelet
membranes by paraprotein & does not depend on
the type of paraprotein presence. I addition
interacting to plt the paraprotein may interfere with
fibrin polymerization and function of other
coagulation protein
o Cardiopulmonary Bypass Surgery
o Liver disease
▪ Chronic alcoholic cirrhosis
▪ Upper Gl bleeding
o Uremia
o Hereditary Afibrinogeniemia
3. Hyperaggregable platelets
QUALITATIVE VASCULAR DISORDERS
ACQUIRED DEFECTS OF PLATELET FUNCTION • DISORDERS AFFECTING THE VESSEL WALL
1. Drug-Induced defects o Vascular hemorrhagic diathesis
o Drugs that inhibits prostaglandin pathway ▪ Henoch-Schonlein purpura
▪ Aspirin and other drugs that inhibit prostaglandin ▪ Hereditary hemorrhagic telangiectasia
synthesis (within 7 days STOP testing) o Thrombotic microangiopathy
o Chronic alcohol consumption ▪ Hemolytic Uremic Syndrome (HUS)
▪ The impaired platelet function seems to be ▪ Thrombotic Thrombocytopenic Purpura
related at least in part to inhibition of o Impaired collagen synthesis
thromboxane synthesis ▪ Scurvy
▪ 3 days NO ALCOHOL INTAKE ▪ Ehlers-Danlos syndrome
o Drugs that inhibit membrane function o Hemangioma-Thrombocytopenia syndrome
o (P2Y12) ADP receptor inhibitor • Henoch-Schonlein Purpura
▪ Steady state is reached 3-5 days o Acquired condition
▪ P2Y12 inhibitors is binding to the platelet o Allergic purpura/ anaphylactoid purpura
membrane STD receptors for ADP and the o Platelet count normal
prevention of ADP binding to those receptors. o Coagulation test normal
o GPIIB/Illa receptor inhibitor o BT/Bleeding Time normal
▪ Interference with the ability of this receptor to o Severe condition, anemia is possible
bind fibrinogen inhibits platelet aggregation o WBC count and ESR is elevated
stimulated in response to all of the usual platelet o “Classic” Clinical Tetrad
aggregating agents. ▪ Non-thrombocytopenia palpable purpura
▪ Abdominal pain (Colicky abdominal pain;
Intussusception (ileoileal); Heme positive stool)
▪ Hematuria (Microscopic Hematuria; Proteinuria,
Elevated BUN/Cr)
▪ Arthritis (Periarticular dse of knees & ankles)

MONTEMOR, DJ 25
 Henoch-Schonlein Purpura tendency, primarily subcutaneous hematoma
• Small-vessel vasculitis formation.
• Deposition of IgA in skin, mucous membranes, kidney, o Easy bruisability, arterial rupture
abdominal vessels
• Most common vasculitis in childhood (2-11 yr)
• White/Asian men >>>everyone else
• Typically preceded by a URI
• 95% full recovery after 3-4wks
• Adult symptoms typically worse
• Renal failure rare but possible
o 5-15% in children
o 30-50% in adults
• Hereditary hemorrhagic telangiectasia o TYPES:
o Telangiectasia – dilated superficial blood vessels ▪ Gravis-EDS classical features
that creates small or coccal red lesion. Occurred ▪ Mitis- Mild expression of classical EDS
throughout the body BUT most obvious in the face, ▪ Hypermobile- Marked joint laxity
lips, tongue, conjunctiva, nasal mucosa, fingers, ▪ Vascular-Severe life-threatening vascular
toes, trunk hemorrhage
o Inherited, autosomal dominant condition. ▪ X-linked-features similar to type Il (different
o AKA (Rendu-Osler-Weber Syndrome) inheritance)
o Characterized by thin-walled blood vessels with a ▪ Ocular/Scoliosis- eye problem
discontinuous endothelium, inadequate smooth ▪ Arthrochalasis- Joint hyperlaxity and congenital
muscle and elastin in the surrounding stroma dislocations
o Patients do well despite lack of specific therapy ▪ Periodontal- Dental problems and classical EDS
Criteria Villefranche Berlin Protein Gene
Epistaxis Spontaneous and recurrent classification Classification Abnormality abnormality
Telangiectasia Multiple, at characteristic sites: lips, oral Classical EDS type I/II Type V collagen COL5A1,
COL5A2
cavity, fingers, and nose Hypermobility EDS type III Unknown Unknown
Visceral lesions Such as gastrointestinal telangiectasia, Vascular EDS type IV Type III collagen CO3A1
or pulmonary, hepatic, cerebra, or Kyphoscoliosis EDS type VI Lysyl hydroxylase PLOD1
spinal AVMs deficiency
Arthrochalasia EDS type Type I collagen COL1A1,
Family history A first-degree relative with HHT VIIA/B COL2A2
according to these criteria Dermatosparaxi EDS type VIIC N-proteinase ADAMST2
HHT diagnosis is s
EDS: Ehlers-Danlos syndrome
Definite If three or more criteria are present
Possible or If two criteria are present • Paraproteinemia
suspected o Abnormality in platelet aggregation, secretion and
procoagulant activity
Unlikely If fewer than two criteria are present
o Acquired condition
Abbreviations: AVM, arteriovenous malformations; HHT,
o Plasma paraprotein and are likely due to coating of
hereditary hemorrhagic telangiectasia.
the platelet membrane with the paraprotein.
Inhibiting adhesion and activation clotting factors on
platelet surfaces.
o Abnormal results of:
▪ PT
▪ aPTT
▪ TT/ Thrombin Time
▪ BT
o Monoclonal Immunoglobin/Immunoglobulin light
chain in the blood or urine – resulting from clonal
proliferation of plasma cells/ B cells
o 3 major disorders associated with Paraproteinemia
▪ MGUS/Monoclonal Gammopathy of
Undetermined Significance
▪ MM/Multiple Myeloma
▪ Waldenstrom

• Hemangioma Thrombocytopenia syndrome

o Inherited condition
o AKA” (Kasabach-Merritt Syndrome)
o Associated with acute or chronic DIC, and
microangiopathic hemolytic anemia.
o Giant cavernous hemangioma (vascular tumor)
leading to thrombocytopenia
o Bleeding diathesis
o Infants, women
• Ehlers-Danlos Syndrome
o Inherited autosomal dominant, recessive or x linked
trait.
o Manifested by hyperextensible skin, hypermobile
joints, joint laxity, fragile tissues, and a bleeding
• Senile Purpura
o Acquired condition
o occurs more commonly in elderly men than in women
o lack of collagen support for small blood vessels and
loss of subcutaneous fat and elastic fibers.
o No bleeding
o BT, CT, Platelet count and clot retraction time normal
o Increased capillary resistance test

MONTEMOR, DJ 26
• Amyloidosis
o The deposition of abnormal quantities of amyloid in
tissues, may be primary or secondary and localized
or systemic
o Fibrous protein consisting of rigid, linear non-
branching aggregated fibrils approx. 7.5 – 10 nn wide
& indefinite length
o Purpura
o Hemorrhage
o Thrombosis
o Abnormal platelet function and sometimes
thrombocytopenia is observed
• Drug Induced Vascular purpuras
o Mechanism includes development of antibody vessel
wall component & development of immune
complexes & changes vessel wall permeability
o Aspirin, warfarin, barbiturates, diuretics, digoxin,
methyldopa, and several antibiotics
o Sulfonamides and iodides have been implicated
most frequently
o Few petechiae to massive petechial eruptions may
vary
o Tx: discontinue drug
• Others/Miscellaneous
o Scurvy
▪ Insufficient dietary intake of vitamin C (ascorbic
acid)
▪ Characterized defective synthesis of collagen &
hyaluronic acid
▪ Symptoms: bleeding of the skin & mucus,
gingivitis, rough / dry skin, joint & body ache,
fatigue, depression, susceptible to infection,
muscle weakness
o Ecchymoses
▪ superficial, bleeding is usually mild, and
laboratory test results are most often normal
• PRACTICE CASE NUMBER 1
o A 23-year-old pregnant women admitted in the
hospital with a past medical history of joint
hyperlaxity and hypermobility. Early onset scoliosis,
recurrent hip and shoulder dislocations and an
absence of dermal, ocular or vascular involvement.
She also has a sister who presented the same
picture but neither parents nor any other relatives
were affected.
o Patient History:
▪ The patient experienced vaginal bleeding.
▪ Normal ultrasound scan
▪ Positive fetal movement and increase dental
instability
▪ Patient experienced ruptured her membranes
▪ Patient has a left hip dislocation which had to be
reduced before induction at 36 hours after
rupture of the membranes. Induction was
performed with oxytocin.
- ANSWER: Ehlers-Danlos syndrome
• PRACTICE CASE NUMBER 2
o A 3-year-old girl presented with severe epistaxis that
had been continuing for approximately 1 hour.
o Patient history:
▪ She experienced no umbilical cord bleeding at
birth but was noticed to bruise easily throughout
infancy and childhood.
▪ At 14 months of age, she experienced recurrent
epistaxis and had approximately 2-3 bleeding
episode each month.
▪ During the presentation to the Physician, the Px
appeared to be well-nourished, playful without
any destress.
o Laboratory Examination:
▪ Microcytic anemia
▪ Normal platelet count, normal PT and aPTT
▪ Hgb: 9 g/dL
▪ MCV: 69 fl
▪ Platelet count: 435,000/ul
▪ Ferritin level: low
▪ Normal PT & aPTT
▪ Platelet aggregation testing: reduced response
to all agonist except for agglutination to
ristocetin.
▪ Platelet Immunophenotyping (Flow Cytometry):
DC41 is low
- ANSWER: Glanzmann thrombasthenia
MONTEMOR, DJ 27