Platelet and Bleeding disorders Flashcards
Screening for Hemostasis
Primary vs Secondary Hemostasis
Primary Hemostasis (“Bruising”)
1) Bleeding time: Tests quality and quantity of platelet function
2) Platelet count
Secondary Hemostasis (“Bleeding”)
3) PT (Prothrombin Time)
Tests function of Extrinsic arm of clotting cascade
4) aPTT (activated Partial Thromboplastin Time)
Tests function of Intrinsic arm of clotting cascade
Bruising Disorders
Usually associated with platelet problems
Bleeding Disorders
Usually associated with coagulation problems
Symptoms Associated with Platelet Disorders
Easy Bruising
Slow, minor bleeding
Bleeding brushing teeth
Menorrhagia
Epistaxis
Petechial rash
platelet disorders
Thrombocytopenia
MOST common symptom is easy bruising and minor bleeding assoc. with minor trauma.
causes of decreased platelet production
Viral infections
HIV, Rubella
Marrow infiltration
Chemotherapy
Vitamin deficiency
B12, Folic Acid
Congenital Defects
Fanconi anemia
Increased platelet destruction causes
Thrombocytopenia of SEQUESTRATION
- Splenomegaly causes an increase in splenic platelet pool and corresponding decrease in peripheral platelet count
- Most commonly seen in congestive splenomegaly assoc with chronic liver disease
- May also occur in other disorders characterized by large spleen (including lymphoma, myelofibrosis)
- Mild anemia or leukopenia may also be seen
immune thrombocytopenic purpura ITP
general
Autoimmune condition resulting in premature destruction of Platelets
Site of destruction
Spleen
Liver
Bone marrow (less common)
Diagnosis of exclusion
ITP
S/Sx
Mucosal bleeding
Epistaxis
Heavy menses
Purpura
Petechiae
ITP
ITP
Laboratory findings
Isolated thrombocytopenia
Anemia, if significant bleeding
Abnormalities in platelet size and morphology
ITP
Bone Marrow Biopsy Indications
Atypical clinical symptoms
Malaise
Lymphadenopathy
Hepatosplenomegaly
Anemia/Leukopenia
**Age **
Age >60 yrs
MDS
Children
Leukemia
Refractory ITP
ITP
Tx
Platelet count >25,000/mcL close observation
Treatment needed if platelet count ≤ 25,000/mcL or significant bleeding
Steroids usual first line treatment
Prednisone with slow steroid taper
Response within 3-7 days but relapse is common during taper
Rituximab (Rituxan)
Intravenous Immunoglobulins
Rapid increase in platelets
Mechanism unknown
Splenectomy
>80% response
Pseudothrombocytopenia
general
Low platelet count due to laboratory artifact
Incompletely mixed or inadequately anticoagulated sample may form clot
Traps platelets in the tube and prevents from being counted
0.1% of population EDTA anticoagulant induces platelet clumping
Platelet autoantibody against concealed epitope on platelet membrane glycoprotein IIb/IIIa
Repeat blood draw with heparin or sodium citrate as anticoagulant
Platelet clumping should not occur
THROMBOTIC Microangiopathies“TMA”
includes and hallmarks of disease
Thrombotic thrombocytopenic purpura (TTP)
Hemolytic uremic syndrome (HUS)
Hallmarks of Disease:
Microangiopathic Hemolytic Anemia (MAHA)
Thrombocytopenia with THROMBOSES
THROMBOTIC Microangiopathies “TMA”
Pentad
Thrombocytopenia
Microangiopathic hemolytic anemia
Renal failure
Neurologic abnormalities
Fever
TMA (TTP and HUS)
Lab features
Anemia
1/3 patients < 6 g/dl
Thrombocytopenia
1/3 patients < 20,000/µL
Reticulocyte count UP
Lactate dehydrogenase (LDH) UP
Haptoglobin DOWN
Coomb’s test usually negative
Fibrinogen normal
Prothrombin time normal
Activated partial thromboplastin time normal
TMA
TTP Specific Dx
TTP:
ADAMTS13 activity levels
Anti-ADAMTS13 autoantibodies
Acquired TTP
TTP Thrombotic Thrombocytopenic Purpura
general
Deficiency in ADAMTS13 activity
Pregnancy
Antibody-mediated
Adults
Rare
95% mortality rate if untreated
HUS
Clinical Presentation
Types
Presents same as TTP EXCEPT:
Not associated w/ ADAMTS13 deficiency
2 types
* Completement Mediated HUS
* Shiga Toxin Mediated HUS
Shiga Toxin Mediated HUS
causes
May follow:
Viral infection
Diarrheal illness
E Coli O157:H7
Shigella dysenteriae
Exposure to
Farm animals
Undercooked meat
Contaminated water
Most common TMA in children
Complement Mediated HUS
general
Hereditary deficiency/abnormality of proteins leading to unregulated complement activation on cell membranes
Acquired form with Complement H factor
Leads to damage of endothelial cells
TMA
Tx
Plasmapheresis for TTP
FFP Transfusion
Steroids
Second line
Rituximab
IVIG
Corticosteroids
**Avoid platelet transfusions!
Worsens TMA
Hematology consultation
Plasmapheresis
Complement mediated HUS
Eculizumab (Soliris) infusion
Anti-complement C5 antibody
Heparin Induced thrombocytopenia “HIT”
General
Acquired disorder
Formation of IgG antibodies to heparin-platelet 4 (PF4) complexes
Bind to and activates platelets
3% of unfractionated heparin patients
0.6% low-molecular-weight heparin (LMWH) patients
HAD to have had a heparin product previously, this reaction is due to a secondary exposure
HIT
RF
Prior heparin use
Long duration of heparin use
Surgery
Pregnancy
Trauma
Inflammatory conditions
HIT
SSx
Typically asymptomatic
Arterial or venous thrombosis
Up to 30 days after diagnosis
Bleeding is rare
Hit (heparin induced thrombocytopenia)
Dx
PF4 heparin antibody testing
Not many places do in house testing of this!
Takes a few days to get results back
HIT
Tx
Consult hematology
Discontinue all heparin products immediately!
Hint: Unfractionated heparin (UFH) is commonly used to flush catheters
Platelet transfusions may increase thrombogenic effect
High risk for thrombotic events
Should be treated with alternative anticoagulants
Initiation of warfarin should be postponed until substantial platelet recovery
HIT
Anticoagulation options
Argatroban weight-based infusion
Direct thrombin inhibitor
Fondaparinux (Arixtra) weight-based once daily injection
Factor Xa inhibitor
Prophylactic anticoagulation should continue until platelets >100,000/mcL
Continue for 30 days
Thrombosis treatment can be changed to warfarin after platelets >100,00/mcL
DOAC (direct oral anticoagulant) use not standard yet
HIT
Long term Tx
Avoid heparin exposure
Document history of HIT in allergies
If heparin products necessary, consult hematology
Will need repeat PF4 antibody levels drawn
Disseminated intravascular coagulation (DIC)
general
Uncontrolled activation of coagulation leading to depletion of coagulation factors and fibrinogen
- Procoagulant substances trigger systemic activation of the coagulation system and platelets
- Disseminated deposition of fibrin-platelet thrombi within the microvasculature
Associated with
Sepsis
Burns
Head trauma
Pregnancy
HELLP syndrome
typically already a very sick patient
DIC
S/Sx
Hallmark is:
Bleeding
Spontaneous bleeding
IV lines
Incisions
Minor trauma
Progressive thrombocytopenia
Thrombosis:
DVT
Digital ischemia
Gangrene
DIC
lab features
Progressive thrombocytopenia
Fibrinogen DOWN
Fibrin degradation products UP
Platelets DOWN
PT / INR UP
PTT normal to UP
D-dimer UP
Peripheral smear
Schistocytes
DIC
TX
treat underlying condition
HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets) in pregnancy
Delivery of fetus
Removal of retained placenta
Give Blood products and factor replacement
Hemophilia
general
bleeding disorder, not platelet disorder
X-linked recessive disorders
Spontaneous cases possible
Hemophilia A– Inherited deficiency of factor VIII
Hemophilia B– Inherited deficiency of factor IX
Hemophilia C – Inherited deficiency of factor XI
Hemophilia A
general
X-linked recessive hereditary disorder of Factor VIII deficiency
2nd most common congenital bleeding disorder
Males almost exclusively affected
Severe = < 1% Factor VIII
Moderate = 1-5% Factor VIII
Mild = > 5% Factor VIII
Inherited deficiency of factor VIII
Males almost exclusively affected
1:4000 births
> ½ with severe disease
Hemophilia A more severe bleeding than B (IX)
Hemophilia A
Clin Man
Spontaneous hemorrhage is hallmark of disease
Hemarthroses 80% of hemorrhagic cases- bleeding into the joint capsule.
Muscle bleeds
GI bleeds
Bleeding tendency—related to severity of deficiency
Older Hemophiliacs may be HIV + due to historically contaminated Factor VIII blood
hemophilia A
Hemarthrosis
hemophilia A
Labs
Laboratory evaluation
Deficient Factor VIII
Prolonged aPTT
Should correct if perform a mixing study
If this does not correct, suggests acquired factor inhibitor
hemophilia A
Tx
Factor VIII concentrate infusion
Recombinant Factor VIII (no HIV risk)
Calculation of Factor VIII dosage related to severity of bleeding. Failure to respond to Factor VIII suggest inhibitor production
Desmopressin may be effective in mild cases (vWF release, carrier of Factor VIII)
Prophylaxis
Emicizumab (Hemlibra) infusion
Monoclonal antibody that binds to both factor IXa and factor X, substituting for the role of factor VIII in hemostasis
AVOID Aspirin!
Hemophilia B
general and Tx
Deficiency Factor IX
1:15,000 to 1:30,000 births
> 1/3 with severe disease
Presents clinically the same as Hemophilia A
Treatment
Factor IX concentrate replacement
Hemophilia B:
Late complications
Hemophilic arthropathy
Infections from plasma products
1970s and 1980s
HIV
50%
Hepatitis C
Most patients
Family & pregnancy planning
Cardiovascular disease
Hemophilia C
general and Tx
Deficiency Factor XI
1:1,000,000 births
Ashkenazi and Iraqi Jews
1:450
Bleeding is variable
Usually no spontaneous bleeding
PTT prolonged in severe deficiency (Factor < 20%)
Treatment
Factor XI replacement
Von Willebrand Disease
general and types (3)
Most common inherited bleeding disorder
VWD
S/Sx
Symptoms:
Type dependent, usually mild
Epistaxis
Easy bruising
Bleeding gums
Heavy menses
Symptoms can range from mild or infrequent bleeding in type 1 VWD to severe, life-threatening bleeding in type 3 VWD
- Mucocutaneous bleeding symptoms
Easy bruising
Prolonged or excessive bleeding from minor injuries
Nosebleeds
GI hemorrhage
Heavy menstrual bleeding - Risk for bleeding following :
Surgery or invasive procedures,
Dental extractions
Traumatic injury
Childbirth
VWD
dont worry about specifics, but helpful!
VWD
Lab results
Platelet count: normal
vWF levels: DOWN or dysfunctional
Bleeding time: typically UP
aPTT: often normal
May be UP if deficiency of Factor VIII
VWD
Tx
Prophylaxis
Prophylaxis
DDAVP (synthetic vasopressin)
Promotes release of vWF from endothelial cells
Replacement therapy
vWF concentrate
Factor VIII concentrate in some patients
Bleeding due to liver disease
clotting factors
Which are k dependent
Liver synthesizes and clears both procoagulants and inhibitors
The hepatocyte is the production site of almost all numbered coagulation factors including fibrinogen (factor I), thrombin (factor II), and upstream factors V, VII, IX, X, and XI
Exceptions
Factor VIII, which is produced in endothelial cells
Factor XIII A-subunit, which is produced in megakaryocytes
Fibrinogen the last to fall
If concurrent Vitamin K deficiency (alcohol use), Affects ALL vitamin K dependent factors (X, IX, VII, and II “1972”)
Liver disease
general
PT (INR) more prolonged than aPTT
Distinguished from simple vitamin K deficiency by failure to respond to vitamin K replacement
Structural manifestations of liver disease contribute to bleeding
Portal hypertension
Esophageal varices
Gastritis
Hemorrhoids
Mechanisms of Vitamin K deficiency
Nutritional depletion
Alcoholics
Long-term IV nutrition
Antibiotic administration
Interfere with bacteria synthesis and absorption
Warfarin
Massive Transfusion
General
Defined as transfusion of more than 1.5 times the patient’s blood volume in 24 h
Acquired coagulopathy results from dilution of plasma and platelets and excess anticoagulant
10% of transfusion is anticoagulant
Prevention:
Administer 1-unit FFP and calcium chloride for every 4-6 units PRBC’s
Hemophilia Therapy
Desmopressin (DDAVP)
MOA: Synthetic analogue of the antidiuretic hormone arginine vasopressin. In a dose dependent manner, desmopressin increases cyclic adenosine monophosphate (cAMP) in renal tubular cells which increases water permeability resulting in decreased urine volume and increased urine osmolality; increases plasma levels of von Willebrand factor, factor VIII, and t-PA contributing to a shortened activated partial thromboplastin time (aPTT) and bleeding time.
Use: DI, Hyponatremia, Hemophilia A, ICH 2’ to antiplatelet agents, vWD
Avoid in moderate to severe renal impairment
Dosage forms: Intranasal, Inj/Infusion, Tablet
Adverse effects: Hyponatremia, xerostomia, fluid retention
Emicizumab (Hemlibra)
MOA: A humanized monoclonal modified immunoglobulin G4 (IgG4) antibody with a bispecific factor IXa- and factor X-directed antibody, bridges activated factor IX and factor X to restore the function of missing activated factor VIII that is needed for effective hemostasis.
Use: Hemophilia A prophylaxis to prevent or reduce the frequency of bleeding episodes with or without factor VIII inhibitors
Initial: 3 mg/kg once weekly for 4 weeks
Maintenance: 1.5 mg/kg once weekly or 3 mg/kg once every 2 weeks or 6 mg/kg once every 4 weeks
Adverse effects: injection site reaction, headache, arthralgia
Avoid in pregnancy (lack of studies)
Hematopoietic Stem Cell Transplant (HSCT)
Potentially curative treatment option for multiple malignant and benign diseases
Also known as bone marrow transplant
Patient receives healthy (unaffected) stem cells to replace their own
Types of Hematopoietic Stem Cell Transplant (HSCT)
Autologous (patient’s own cells)
Allogeneic
cells from another person
Sibling
Parent or relative
Unrelated Donor
Source
Umbilical cord
Peripheral blood
Bone marrow
indications for AUTOlogous stem cell transplant
indications for allogenic transplant
HSCT Process
1.Conditioning
2.Stem cell infusion
3. Neutropenic phase
4. Engraftment phase
5. Post-engraftment period
Graft versus Host Disease (GVHD)
If donor cells see the host cells as foreign, they will attack the host
Skin, gut, and liver most likely to be affected
Acute < 100 days after the transplant
Chronic > 100 days
