Coagulation and platelet Flashcards
normal hemostasis is a Precisely orchestrated process involving ___________________ that occur at the site of vascular injury and
culminates in the formation of blood clot, which
serves to prevent or limit the extent of bleeding.
platelets, clotting factors, and endothelium
STEPS IN HEMOSTASIS
ARTERIOLAR VASOCONSTRICTION
PRIMARY HEMOSTASIS
SECONDARY HEMOSTASIS
CLOT STABILIZATION AND RESORPTION
Occurs immediately and markedly reduces blood
flow to the injured area
ARTERIOLAR VASOCONSTRICTION
Reflex neurogenic mechanism
ARTERIOLAR VASOCONSTRICTION
Disruption of endothelium exposes _____ and _____,
which promote platelet adherence and activation, this is beginning of primary hemostasis
vWF and collagen
Activation of platelet results in
dramatic shape
change as well as release of secretory granules
Within a few minutes, the secreted products
recruit additional platelets that undergo
aggregation to form a primary hemostatic plug
primary hemostasis
Vascular injury exposes tissue factors at the site
of injury
Tissue factors binds and activates factor VII,
setting in motion a cascade of reactions that
culminates in thrombin generation.
SECONDARY HEMOSTASIS
cleaves fibrinogen into insoluble fibrin
and activates platelets (2ndary)
thrombin
consolidates the initial platelet plug
secondary hemostasis
Polymerized fibrin and platelet aggregates
undergo contraction to form a solid, permanent
plug
CLOT STABILIZATION AND RESORPTION
At this stage, counter-regulatory mechanisms (tPA) are set into motion that limit clotting to the site
of injury and eventually lead to clot resorption and
tissue repair.
CLOT STABILIZATION AND RESORPTION
Excessive bleeding can result from:
- Increased fragility of vessels
- Platelet deficiency or dysfunction
- Derangement of coagulation, alone or in
combination
The normal hemostatic response involves the
blood vessel wall, the platelets, and the
clotting cascade
Assesses the extrinsic and common coagulation
pathways (factors VII, X, V, II [prothrombin], and
fibrinogen)
PROTHROMBIN TIME (PT) 7,10,5,2
Prolonged PT can result from deficiency or
dysfunction of
factor V, factor VII, factor X, prothrombin, or fibrinogen
Assesses the intrinsic and common clotting
pathways (factors XII, XI, IX, VIII, X, V, II, and
fibrinogen)
PARTIAL THROMBOPLASTIN TIME (PTT)
12, 11, 10, 9, 8, 5, 2
fibrinogen)
Prolongation of the PTT can be due to deficiency
or dysfunction of factors
V, VIII, IX, X, XI, or XII,
prothrombin, or fibrinogen, or to interfering
antiphospholipid antibodies
platelet reference range
150x10^3 to 350x10^3
platelets/uL
platelet High counts may be indicative of a
myeloproliferative neoplasm, but are more likely
to reflect reactive processes that increases platelet production
T or F
No single test provides an adequate assessment
of the complex function of platelet
T
Test of platelet fx
Tests of platelet aggregation
Quantitative and qualitative test of von Willebrand factor
Bleeding time-
infections which Often induce petechial and purpuric hemorrhages
meningococcemia, other forms of septicemia infective endocarditis and several of the rickettsioses
Infection induced petechial and purpuric hemorrhage mechanism
Microbial
damage to the microvascular (vasculitis) and disseminated intravascular coagulation
vascular injury is mediated by the deposition of drug
induced immune complexes in vessel walls,
leading to
hypersensitivity (leukocytoclastic)
vasculitis
Associated with microvasculature bleeding due to
collagen defects that weaken vessel walls.
SCURVY AND THE EHLERS-DANLOS SYNDROME
HENOCH-SCHONLEIN PURPURA is Systemic immune disorder characterized by
purpura, colicky abdominal pain, polyarthralgia, and acute
glomerulonephritis
result from the deposition of circulating immune complexes within vessels
throughout the body and within the glomerular
mesangial regions
HENOCH-SCHONLEIN PURPURA
Autosomal dominant disorder that can be caused by mutations in at least five different genes, most of which modulate TGF-B Signaling
HEREDITARY HEMORRHAGIC
TELANGIECTASIA (WEBER OSLER-RENDU SYNDROME
Dilated , tortuous blood vessels with thin walls
that bleed readily
HEREDITARY HEMORRHAGIC
TELANGIECTASIA (WEBER OSLER-RENDU SYNDROME
in HEREDITARY HEMORRHAGIC
TELANGIECTASIA (WEBER OSLER-RENDU SYNDROME, Bleeding can occur anywhere , but it is most
common
under the mucous membranes of the
nose (epitaxis), tongue, mouth,and eyes and
through gastrointestinal tract
Weaken blood vessel walls and cause bleeding
This complication is most common with amyloid light chain (AL) amyloidosis and often manifests as mucocutaneous petechiae.
PERIVASCULAR AMYLOIDOSIS
Among these conditions, serious bleeding is most
often associated with
HEREDITARY HEMORRHAGIC
TELANGIECTASIA (WEBER OSLER-RENDU SYNDROME
Bleeding disorders due to vessel wall abnormalities
Infections Drug Rxns Scurvy and the ehlers-danlos syndrome Henoch-schonlein pupura HEREDITARY HEMORRHAGIC TELANGIECTASIA (WEBER OSLER-RENDU SYNDROME PERIVASCULAR AMYLOIDOSIS
Count less than________ is generally
considered to constitute thrombocytopenia.
150,000 platelets /ul
can aggrevate
posttraumatic bleeding.
20,000 to 50000 platelets/ul
When thrombocytopenia is isolated, the PT and
PTT are
normal
causes of thrombocytopenia
Decreased platelet production
Decreased platelet survival
Sequestration
Dilution
`causes decreased platelet production
Conditions that depress marrow output generally or affect megakaryocytes selectively. Certain drugs and alcohol HIV, which may infect megakaryocytes and inhibit platelet production. Myelodysplastic syndrome.
is caused by the
deposition of antibodies or immune complexes on platelets
Immune thrombocytopenia
non immunologic causes of thrombocytopenia
o Disseminated intravascular coagulation
(DIC) and the thrombotic microangiopathies.
o Mechanical injury such as individuals with
prosthetic heart valves
platelet _____ can rise to 80% to 90% when the spleen is
enlarged , producing moderate degress of
thrombocytopenia
Sequestration
Massive transfusions can produce dilutional
thrombocytopenia.
Dilution
Autoantibody mediated destruction of platelets
It can occur in the setting of a variety of predisposing
conditions and exposures(secondary) or in the
absence of any known risk factors( primary or
idiopathic)
CHRONIC IMMUNE THROMBOCYTOPENIC PURPURA
CITP pathogenesis
Auto-antibodies , against glycoproteins IIb-IIIa or Ib-IX , can be demonstrated in the plasma and
bound to the platelet surface in about 80% of the
patients
CITP spleen morphology
normal size.
congestion of the sinusoids
enlargement of the splenic follicles
often associated with prominent reactive germinal centers.
CITP marrow morphology
modestly increased
number of megakaryocytes. Some are apparently
immature with large, non-lobulated , single nuclei.
CITP peripheral blood morphology
abnormally
large platelets.
CITP female to male ratio
3:1
Pinpoint hemorrhages (petechiae) are especially
prominent in the dependent areas where the
capillary pressure is
higher
Typical laboratory findings (CITP)
o Low platelet count
o Normal or increased megakaryocytes in the
bone marrow and large platelets in the
peripheral blood
o PT and PTT are normal
o Tests for platelet autoantibodies suffer from
low sensitivity and specificity and are not
clinically useful.
o Therefore, the diagnosis is one of the
exclusion and can be made only after other
causes of thrombocytopenia have been ruled
out
CITP treatment
Respond to glucocorticoids Splenectomy (severe thrombocytopenia) Immunomodulatory agents such as IV immunoglobulin or anti-CD20 antibody (rituximab) are often effective
T or F
AITP is Mainly a disease of childhood occurring with
equal frequency in both sexes.
T
AITP symptoms occur
Often 1 to 2 weeks after a self-limited
viral illness
AITP is usually resolved within
6 months
drugs most commonly implicated in DIT
quinine (anti-malarial), quinidine (antiarrhythmic), and vancomycin (antibiotic)
Thrombocytopenia, which may be severe, can
occur in those who are taking
platelet inhibitory
drugs that bind glycoprotein IIb/IIIa (ex.
abciximab, tirofiban)
Thrombocytopenia occurs in about 5% of persons
receiving heparin and is of two types:
o Type I HIT
o Type II HIT
Occurs rapidly after the onset of therapy and is of little clinical importance, sometimes resolving despite the continuation of therapy.
o Type I HIT
It most likely results from a direct platelet-aggregating effect of heparin.
o Type I HIT
Occurs 5 to 14 days after therapy begins (or sooner if the person has been sensitized to heparin)
and, paradoxically, often leads to venous and arterial thrombosis.
o Type II HIT
Caused by antibodies that
recognize complexes of heparin and platelet factor 4, a normal component of platelet granules.
o Type II HIT
receptor and co-receptor,
respectively, for HIV, are found on megakaryocytes, allowing these cells to be
infected
CD4 and CXCR4
HIV-infected megakaryocytes are prone to
apoptosis
HIV infection also causes B-cell
hyperplasia and
dysregulation
THROMBOTIC MICROANGIOPATHIES
TTP & HUS
Clinical syndromes that are caused by insults that
lead to excessive activation of platelets, which deposit
as thrombi in small blood vessels
THROMBOTIC MICROANGIOPATHIES
Defined as the pentad of fever,
thrombocytopenia, microangiopathic
hemolytic anemia, transient neurologic
deficits, and renal failure.
THROMBOTIC THROMBOCYTOPENIC PURPURA
TTP
Also is associated with microangiopathic
hemolytic anemia and thrombocytopenia but
is distinguished by the absence of
neurologic symptoms, the prominence of
acute renal failure, and its frequent
occurrence in children.
HEMOLYTIC UREMIC SYNDROME (HUS)
THROMBOTIC THROMBOCYTOPENIC PURPURA
Caused by a deficiency in a plasma enzyme called
ADAMTS13, also designated “vWF metalloprotease.”
ADAMTS13 degrades
very high-molecular-weight multimers of vWF
T or F
In its absence (ADAMTS13), large multimers accumulate in plasma
and tend to promote spontaneous platelet activation
and aggregation.
T
- an autoantibody that inhibits the
metalloprotease activity of ADAMTS13 is
present.
Acquired
the onset is often delayed until adolescence, and the symptoms are episodic.
Thus, factors other than ADAMTS13 deficiency (e.g., a superimposed
vascular injury or prothrombotic
state) must be involved in triggering
full-blown TTP.
Hereditary
removes
autoantibodies and provides functional ADAMTS13,
TTP (which once was uniformly fatal) can be treated successfully in more than 80% of patients
plasma exchange
Strongly associated with infectious
gastroenteritis caused by Escherichia coli
strain O157:H7, which elaborates a Shigalike toxin.
“Typical” HUS
Defects in complement factor H, membrane
cofactor protein (CD46), or factor I, proteins
that act to prevent excessive activation of the
alternative complement pathway.
“Atypical” HUS
BLEEDING RELATED TO REDUCED PLATELET
NUMBER: THROMBOCYTOPENIA
CHRONIC IMMUNE THROMBOCYTOPENIC PURPURA
ACUTE IMMUNE THROMBOCYTOPENIC PURPURA
DRUG-INDUCED THROMBOCYTOPENIA
HEPARIN-INDUCED THROMBOCYTOPENIA
HIV-ASSOCIATED THROMBOCYTOPENIA
THROMBOTIC MICROANGIOPATHIES: TTP & HUS
THROMBOTIC THROMBOCYTOPENIC PURPURA
HEMOLYTIC UREMIC SYNDROME (HUS)
BLEEDING DISORDERS RELATED TO DEFECTIVE
PLATELET FUNCTION
BERNARD-SOULIER SYNDROME
GLANZMANN THROMBASTHENIA
STORAGE POOL DISORDERS
INGESTION OF ASPIRIN AND OTHER NSAID
Inherited disorders of platelet function can be
classified into three pathogenically distinct groups:
- Defects of adhesion
- Defects of aggregation
- Defects of platelet secretion (release reaction)
Defective adhesion of platelets to subendothelial
matrix
BERNARD-SOULIER SYNDROME
BERNARD-SOULIER SYNDROME
is an Inherited deficiency of the platelet membrane
glycoprotein complex
Ib-IX
This glycoprotein is a receptor for vWF and is
essential for normal platelet adhesion to the
subendothelial extracellular matrix
glycoprotein complex Ib-IX
bernard soulier syndrome clinical manifestations:
variable, often severe,
bleeding tendency.
Bleeding due to defective platelet aggregation
GLANZMANN THROMBASTHENIA
GLANZMANN THROMBASTHENIA
- Platelets fail to aggregate in response to ADP,
collagen, epinephrine, or thrombin because of
deficiency or dysfunction of
glycoprotein IIb-IIIa
Characterized by the defective release of certain
mediators of platelet activation, such as
thromboxanes and granule-bound ADP.
STORAGE POOL DISORDERS
s a potent, irreversible inhibitor of
cyclooxygenase, an enzyme that is required for the
synthesis of thromboxane A2 and prostaglandins.
aspirin
BLEEDING DISORDERS RELATED TO
ABNORMALITIES IN CLOTTING FACTORS
HEREDITARY DEFICIENCIES ACQUIRED DEFICIENCIES FACTOR VIII-vWF COMPLEX VON WILLEBRAND DISEASE HEMOPHILIA A (FACTOR VIII DEFICIENCY) HEMOPHILIA B (CHRISTMAS DISEASE, FACTOR IX DEFICIENCY) DISSEMINATED INTRAVASCULAR COAGULATION (DIC)
Bleeding due to coagulation factor deficiencies
commonly manifest as
large posttraumatic
ecchymoses or hematomas, or prolonged bleeding
from a laceration or after a surgical procedure
The most common and important inherited
deficiencies of coagulation factors affect
factor 8
hemophilia A) and factor 9 (hemophilia B
Vitamin K deficiency impairs the synthesis of
factors II, VII, IX, X and protein C
All coagulation factors are produced in the liver
except____ which is produced by endothelial
cells.
factor VIII (8)
are caused by qualitative or quantitative defects
hemophilia A and von Willebrand disease
aids F IX in activation of F X.
F VIII-VWF
o Essential cofactor of factor IX, which converts F
X to FXa
o Binds to and is stabilized by vWF, an interaction
that increases the half-life of F VIII from about
2.4 hours to about 12 hours.
Factor VIII
o Secreted into the circulation by endothelial cells
o Function in stabilization of FVIII
vWF
promote adhesion of platelets to the
subendothelial matrix
vWF
vWF also may promote platelet aggregation by
binding to activated
GpIIb/IIIa integrins
vWF function is assessed using the
Ristocetin
agglutination test
The most common symptoms: Spontaneous bleeding from mucous membranes (e.g. epistaxis), excessive bleeding from wounds, menorrhagia It is usually transmitted as an autosomal dominant disorder
VON WILLEBRAND DISEASE
AD (autosomal dominant) disorder characterized by a mild to moderate vWF
deficiency
Type 1 and Type 3 von Willebrand disease
– is associated with a spectrum of
mutations, including point substitutions
that interfere with maturation of the vWF
protein or that result in rapid clearance
from plasma; this disorder is mild; there
is still production of vWF
type 1 vWF disease
disease is an autosomal disorder usually caused by deletions or frameshift mutations involving both alleles, resulting in little to no vWF synthesis; mutations here are bigger, more severe
type 3vWF disease
the most common subtype in type 2 VWF disease
2a
vWF is expressed in normal amounts, but missense mutations are present that
lead to defective multimer
assembly.
Type 2 von Willebrand disease
accounts for 25% of all cases and is associated
with mild to moderate bleeding.
Type 2 von Willebrand disease
T or F
Type 2 vWF is Associated with a prolonged PTT
T (intrinsic)
Type 1 or 2 vWF tx
can be treated with
desmopressin as a prophylactic
measure, or infusions of plasma concentrates containing factor VIll and
vWF, or with recombinant vWF.
must be treated prophylactically with plasma concentrates and factor VIll infusions to prevent severe "hemophilia-like" bleeding.
Type 3 disease
Most common hereditary disease associated with
life-threatening bleeding
HEMOPHILIA A (FACTOR VIII DEFICIENCY)
is inherited as an X-linked
recessive trait and thus affects mainly males and
homozygous females.
Hemophilia A
Most severe deficiencies result from an
inversion involving the X chromosome that
completely abolishes the synthesis of factor VIll.
T or F
In Factor VIII deficiency, Petechia are characteristically absent
T
Hemophilia a TREATMENT
Infusions of recombinant factor VIll.
Recently, bispecific antibodies have been
developed that bind factor IXa to factor X;
these antibodies bypass the need for factor
VIll and are particularly effective in patients
with factor VIII antibody inhibitors
A wide spectrum of mutations involving the gene that
encodes factor IX is found in
hemophilia B
T or F
Hemophilia B is X-linked recessive trait like hemophilia A
T
Hemophilia b Diagnosis is possible only by
assay of the factor
levels, that’s the only way to differentiate them, you
have to assay or do a mixing studies between factor
8 and 9 but clinically they are the same
T or F
In hemophilia B, PTT is prolonged and PT is normal
T
