Term
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Definition
includes any disorders of coagulation
can be hypercoagulable or hypocoagulable states |
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Term
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Definition
treated with anticoagulants
CONGENITAL:
factor V Leiden
prothrombin gene mutation
elevated homocysteine
protein C or S deficiency
dysfibrinogenemia
ACQUIRED:
cancer
trauma
hemostasis
pregnancy
drugs
disseminated intravascular coagulation (DIC) |
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Term
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Definition
CONGENITAL:
hemophilia
von Willebrand disease
other factor deficiencies
ACQUIRED:
vitamin K deficiency
coagulopathy and liver disease (in severe liver disease, blood factors are not created) |
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Term
| variable coagulable states |
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Definition
thrombocytopenia
HYPERCOAGULABLE:
HIT - antibodies on platelets; the thrombocytes will clump and thrombosis will form throughout the body
thrombotic cytopenia purpurae
HYPOCOAGULABLE:
ideopathic thrombocytopenia purpurae - body makes antibodies against platelets which are cleared by the spleen
myeloproliferative disorders
drug induced myelosuppression |
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Term
| coagulation disorders can result from: |
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Definition
decreased number of platelets
decreased function of platelets
coagulation factor deficiency
enhanced fibrinolytic activity |
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Term
| diagnosis of coagulation disorders |
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Definition
patient history
physical examination
family history
laboratory tests:
bleeding time
prothrombin time (PT)
activated partial thromboplastin time (aPTT)
thrombin time
platelet count |
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Term
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Definition
time to cessation of bleeding following a standardized skin cut
assesses platelet and capillary function |
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Term
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Definition
assesses function of the extrinsic system and common pathway in the coagulation system (vitamin K dependent proteins: II, VII, IX, X, and proteins C and S)
expressed as international normalized ratio (INR) to account for variability of the test reagents
INR used for monitoring warfarin therapy |
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Term
| activated partial thromboplastin time (aPTT) |
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Definition
measures the activity of the intrinsic system and common pathway (II, V, X, VIII, IX, XI, XII high molecular weight kinnogen, prekallikrein, and fibrinogen)
used for monitoring heparin therapy |
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Term
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Definition
DEFINITION: bleeding disorder that results from congenital deficiency in a plasma coagulation protein
TYPES:
hemophilia A (classic hemophilia) - deficiency of factor VIII; 1 in 5,000 male births
hemophilia B (less common) - deficiency of factor IX; 1 in 30,000 male births
spontaneous (30%) or inherited: recessive X-linked disease |
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Term
| signs and symptoms of hemophilia |
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Definition
ECCHYMOSES - escape of blood into the tissues from ruptured blood vessels
HEMARTHROSIS - blood deposits in the joints; hallmark symptom of hemophilia; most common in knees and elbows; may lead to degenerative joint disease (pain, difficulty in mobility)
joint pain, swelling, erythema
decreased range of motion
MUSCLE HEMORRHAGE
swelling
pain with motion of affected muscle
signs of nerve compression
potential life threatening blood loss
bleeding with dental extractions or trauma
genitourinary bleeding
hematuria
intracranial hemorrhage
EXCESSIVE BLEEDING WITH SURGERY |
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Term
| hemophilia laboratory tests |
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Definition
prolonged aPTT
decreased factor VIII/factor IX level
1 U/mL = 100% of factor found in 1 mL of normal plasma
normal PT
normal platelet count
normal von Willebrand factor antigen and activity |
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Term
| laboratory and clinical manifestations of severe hemophilia |
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Definition
severe (< 0.01 U/mL = 1%)
age at onset < 1 year
neonatal symptoms:
usually postcircumcisional bleeding
occasionally intracranial hemorrhage
spontaneous muscle/joint hemorrhage
post surgical hemorrhage (w/o prophylaxis) = frank bleeding, severe
usual oral hemorrhage following trauma, tooth extraction |
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Term
| laboratory and clinical manifestations of moderate hemophilia |
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Definition
moderate (0.01-0.05 U/mL = 1%-5%)
age at onset 1-2 years
neonatal symptoms:
usually postcircumcisional bleeding
uncommonly intracranial hemorrhage
minor trauma leads to muscle/joint hemorrhage
post surgical hemorrhage (w/o prophylaxis) - wound bleeding common
common oral hemorrhage following trauma, tooth extraction |
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Term
| laboratory and clinical manifestations of mild hemophilia |
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Definition
mild (> 0.05 U/mL)
age at onset 2 years-adult
neonatal symptoms:
rare postcircumcisional bleeding
rare intracranial hemorrhage
minor trauma leads to muscle/joint hemorrhage
post surgical hemorrhage (w/o prophylaxis) - wound bleeding with factor < 0.3 U/mL
often oral hemorrhage following trauma, tooth extraction |
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Term
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Definition
male with unusual bleeding
FH of bleeding
hemophilia A: test for common factor VIII gene inversions
hemophilia B: direct DNA mutational analysis
screening:
brothers of hemophiliacs should be screened
sisters should have carrier testing
prenatal diagnosis:
chorionic villus sampling (10th-11th gestational week)
amniocentesis (>15 weeks gestation) |
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Term
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Definition
routine immunizations + hepatitis A and B (use small gauge needles to prevent excessive bleeding)
perinatal care of male infants of hemophilia carriers:
AVOID use of vacuum extraction and forceps delivery if possible
postpone circumcision until diagnosis is excluded
assay factor levels from cord blood or peripheral venipuncture
DOC: intravenous factor replacement |
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Term
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Definition
derived from cultured Chinese hamster ovary cells or baby hamster kidney cells transfected with the human factor VIII gene
risk of transmitting infection low
no hepatitis or HIV ever reported
parvovirus B19 reported
generations (stabilizing agents)
albumin -> sucrose (with albumin in culture) -> no human protein (currently used)
efficacy comparable to plasma derived
risk of inhibitory antibody to factor VIII: 28%-33%
recombinant is JUST factor VIII; plasma derived has other things in it (like vWF) |
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Term
| plasma derived factor VIII |
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Definition
derived from the plasma of thousands of donors
potential to transmit infection
infection prevention as with the blood supply
no cases of HIV transmission since 1986
hepatitis C cases have been reported
hepatitis A outbreaks reported
parvovirus reported
some products have vWF as well (Humate, Alphanate)
products that are ultra pure are depleted of vWF; vWF is good for platelet adhesion and this is beneficial in hemophilia patients |
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Term
| things that affect hemophilia A therapy |
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Definition
half life of the infused factor (half life of VIII is 8-12 hours)
patient's body weight
volume of distribution
presence and titer of inhibitory antibody to factor VIII |
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Term
| hemophilia A therapy: other pharmacologic therapy |
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Definition
DESMOPRESSIN ACETATE
minor bleeding episodes (mild hemophilia A)
MOA: causes release of vWF and factor VIII from endogenous storage sites
desmopressin trial: at least a twofold rise in factor VIII (minimum 0.3 U/mL) within 60 minutes is adequate response
ADRs: facial flushing, HA, tachycardia, hypotension, water retention/hyponatremia |
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Term
| hemophilia A therapy: antifirinolytics |
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Definition
inhibition of clot lysis (inhibit plasminogen)
useful as adjunctive therapy, particularly for oral bleeding
aminocaporic acid (IV/PO = using IV form orally)
tranexamic acid |
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Term
| hemophilia B therapy: recombinant factor IX |
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Definition
derived from cultured Chinese hamster ovary cells transfected with the human factor IX gene
no blood/plasma products used
higher doses must be used to achieve equivalent plasma levels (compared to plasma derived)
individual PK may vary, so recovery and survival studies should be performed to determine optimal treatment
considered DOC for hemophilia B |
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Term
| hemophilia B therapy: plasma derived factor IX |
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Definition
high purity
derived from plasma through biochemical purification and monoclonal immunoaffinity techniques
viral inactivation
excellent efficacy in the control of bleeding
excellent viral safety profile
low risk of thromboembolic complications |
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Term
| hemophilia B therapy: prothrombin complex concentrates (PCCs) |
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Definition
factor IX concentrate that also contains factors II, VII, and X
ADRs: thrombotic complications (DVT, PE, MI, disseminated intravascular coagulopathy)
high risk patients: high or repeated doses, liver disease, neonates, crush injuries/surgery
do NOT administer with antifibrinolytic
used in patients with inhibitory antibodies against factor VIII or IX |
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Term
| prophylactic factor replacement therapy |
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Definition
regular infusion of concentrate to maintain the deficient factor at a minimum of 0.01 U/mL (1%)
ideally keep at > 2%
primary: prior to onset of joint bleeding (<2 years)
secondary: after significant joint bleeding has occurred
converting severe hemophilia into a milder form of disease (prevention of hemarthrosis) |
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Term
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Definition
| dose = weight (kg) x (desired % increase) x 0.5 |
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Term
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Definition
inhibitors = neutralizing antibodies to factor VIII and IX
most common serious complication of factor replacement therapy
prevalence: increased with severe hemophilia; A>B
measurement: 1 bethesda unit (BU) = amount of inhibitor needed to inactivate half of the factor
patient with inhibitors:
low responders: < 5 BU/mL
high responders: > 5 BU/mL |
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Term
| treatment of patients with inhibitors |
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Definition
approach to treatment:
inhibitor titer
site and magnitude of bleeding
patient's past response to therapy
low inhibitor titer:
2-3 x usual replacement dose
more frequent dosing intervals
high inhibitor titer:
prothrombin complex concentrates (PCCs)
recombinant activated factor VII
porcine factor VIII (alternative) |
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Term
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Definition
hemostatically active only at the site of tissue injury where tissue factor is present
minimal risk of systemic thrombotic events
not plasma derived
short t1/2 - dosing q2h
continuous infusion appears efficacious, but studies limited |
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Term
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Definition
immune tolerance therapy:
scheduled infusion of high doses of factor
adjunctive immunomodulatory therapy:
cyclophosphamide
prednisone
IV immune globulin
rituximab:
anti-CD20 monoclonal antibody
used in a few patients with factor VIII inhibitors
MOA: rapid depletion of circulating B cells that produce antibodies |
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Term
| hemophilia pain management |
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Definition
acute pain: cause = bleeding; treatment = control bleeding
chronic pain:
cause = permanent joint changes
treatment:
surgical intervention
intensive physical therapy
intra-articular dexamethasone injection
mild pain - acetaminophen
severe pain - narcotics
chronic arthropathy - COX2 inhibitors? STAY AWAY FROM NSAIDS! |
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Term
| hemophilia therapeutic outcomes |
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Definition
goal: control and prevent bleeding episodes and their long term sequelae
monitoring:
cessation of bleeding
resolution of symptoms
plasma factor levels
patient diaries
physical exam
inhibitor titers |
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Term
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Definition
2 types:
type A - factor VIII deficiency
type B - factor IX deficiency
causes bleeding, hemarthrosis is typical hallmark symptom
treatment is replacement with factors
goal minimum factor level is 1%, unless event
patients may develop inhibitors to factors |
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Term
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Definition
most common congenital bleeding disorder
prevalence 1-2%
family of disorders caused by defect of von Willebrand factor, a glycoprotein involved in coagulation and platelet function
autosomal inheritance (male = female)
carriers may be symptomatic "mild vW disease)
vWF:
promotes platelet adhesion (platelet glycoprotein Ib receptor)
facilitates platelet aggregation (platelet glycoprotein IIb/IIIa receptor)
carrier molecule for factor VIII preventing premature degradation and removal |
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Term
| von Willebrand disease classification |
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Definition
Type 1: 60-75%, least severe
Type 2: 9-30%, 4 subtypes
Type 3: <10%, most severe form
acquired: antibodies to vWF
related to autoimmune disorders (i.e. lupus)
medications (valproic acid, cipro) |
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Term
| clinical presentation of vWD |
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Definition
variable
mucocutaneous bleeding:
epistaxis
gingival bleeding with minor manipulation
menorrhagia
easy bruising
postoperative bleeding |
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Term
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Definition
patient history of mucocutaneous bleeding
family history of abnormal bleeding
initial screening tests:
PT (normal)
aPTT (prolonged if factor VIII decreased)
bleeding time (normal - prolonged)
platelet count (normal; decreased with type 2B and platelet type pseudo-vWD)
specific tests:
vWF antigen
factor VIII assay
Ristocetin cofactor activity
vWF multimer analysis |
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Term
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Definition
considerations:
type of vWD
location and severity of bleeding
superficial bleeding:
local measures (pressure, ice, topical thrombin)
systemic treatment:
used - uncontrolled bleeding, surgery prophylaxis (including prior to delivery)
goal - correct platelet adhesion and coagulation defects; stimulate release of endogenous vWF; administer vWF and factor VIII |
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Term
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Definition
stimulates endothelial release of vWF and factor VIII
effective:
most with type 1
some with type 2A |
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Term
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Definition
virus inactivated, intermediate or high purity factor VIII concentrations contain sufficient amount of vWF (such as Humate or Alphanate)
ultra high purity (monoclonal antibody derived) and recombinant factor VIII products contain negligible amounts
recombinant factor VIII cannot be given b/c it does not contain vWF
plasma derived has vWF EXCEPT if it is ultrapurified, then it does not |
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Term
| other treatment options for vWD |
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Definition
antifibrinolytic agents:
tooth extractions
epistaxis
GI bleeding
menorrhagia
avoid in urinary tract bleeding |
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Term
| idiopathic thrombocytopenia purpura |
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Definition
characterized by thrombocytopenia that is an acquired and generally benign disorder of unknown cause
acute ITP is the form most commonly seen in children, whereas the chronic form is more common in adults
in ITP, autoantibodies (usually IgG) are directed against platelet membrane antigens
the antibody-coated platelets have a shortened half life
accelerated clearance by tissue macrophages in the spleen
most common cause of symptomatic thrombocytopenia in children
usually present between 2 and 10 years of age
slight predominance of boys to girls |
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Term
| clinical manifestations of ITP |
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Definition
if symptoms other than bleeding are present, another cause of thrombocytopenia should be strongly considered
should review any drug use: heparin, quinidine, sulfonamides, famotidine, linezolid
no symptoms potentially
mild symptoms: bruising and petechiae, occasional minor epistaxis, very little interference with daily living
moderate: more severe skin and mucosal lesions, more troublesome epistaxis and menorrhagia
severe: bleeding episodes menorrhagia, epistaxis, melena requiring tranfusion or hospitalization, symptoms interfering seriously with the quality of life |
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Term
| bleeding and platelet count in ITP |
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Definition
platelet count 50,000 and below:
1. minimal bleeding after trauma
platelet count 40,000 and below
2. spontaneous but self limited bleeding
platelet count 20,000 and below
3. spontaneous bleeding requiring special attention
platelet count 10,000 and below
4. severe, life threatening bleed |
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Term
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Definition
isolated thrombocytopenia, with otherwise normal blood counts and peripheral blood smear
no clinically apparent associated conditions that may cause thrombocytopenia
the presenting platelet count is usually less than 20,000
no morphologic abnormalities in the white or red blood cells
antiplatelet antibody testing:
high sensitivity, lack specificity
not routinely indicated
bone marrow examination:
normal appearance and numbers of erythroid and myeloid precursors
normal to increased numbers of megakaryocytes
DIFFERENTIAL DIAGNOSIS:
active infection
drug exposure
autoimmune disease
leukemia
acquired bone marrow failure syndromes |
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Term
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Definition
INITIAL MANAGEMENT:
supportive care: restriction of activity, avoid medications with antiplatelet activity
pharmacologic intervention:
presence of severe or life threatening bleeding
risk of significant bleeding, such as a child undergoing a procedure that is likely to induce blood loss
any concomitant or preexisting condition that increases the risk of thrombocytopenia or bleeding (e.g. hemophpilia)
if life threatening bleed, immediately give platelets; if the bleed is not life threatening, do not give them platelets b/c the body will clear them within 12-24 hours
administration of platelets in ITP is only given in life threatening situation, other treatments are to prevent antibody production or activity
treatments:
corticosteroids
intravenous immunoglobulin (IVIG)
intravenous anti-rH (d) immune globulin
rituximab
thrombopoietin analogues
speenectomy |
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Term
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Definition
reducing antibody production
reducing reticuloendothelial system phagocytosis of antibody-coated platelets
improving vascular integrity
improving platelet production
GI prophylaxis should be considered |
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Term
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Definition
induces a rapid rise in platelet count
thought to prevent antibody binding to platelets by blocking the Fc receptor
ADRs:
hypotension
fever
diarrhea
N/V
arthralgias and myalgias |
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Term
| anti-Rh immune globulin (WinRho) |
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Definition
intravenous anti-Rh therapy
binds to RBCs which are then preferentially attacked by macrophages
ADRs:
hemolysis (anemia)
headache
N/V |
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Term
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Definition
premedicate with APAP and diphenydramine
approximately 60% of patients will respond, 40% will have long term response
ADRs:
fever
hypotension
night sweats
N/V/D
anaphyalxis |
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Term
| thrombopoietin analogues for ITP |
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Definition
eltromobopag (po)
romiplostim
eltromobopag generally better tolerated
used for chronic therapy
ADRs:
HA
increased LFTs
N/V
arthralgias and myalgias |
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Term
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Definition
splenectomy - generally reserved for refractory patients
platelet transfusions - generally not done unless platelets are very low, or active bleeding |
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Term
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Definition
persistent 6 months after presentation
thrombocytopenia < 150,000
pharmacologic therapy:
usually is used when patients have significant bleeding, or require surgery or dental extraction
corticosteroids
immunoglobulin therapy |
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Term
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Definition
children recover spontaneously (weeks to months of treatment)
in adults spontaneous remission is rare |
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Term
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Definition
acute episode:
corticosteroids, if ineffective
IVIG, if ineffective
WinRho, if ineffective
rituximab, if ineffective
chronic:
splenectomy, if ineffective
TPO analogues |
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