Bleeding Disorders Flashcards
Causes of Excessive Bleeding
- Increased vessel fragility
- Platelet deficiency or dysfunction
- Derangement of coagulation
Laboratory Coagulation Tests
Primary Hemostasis
- Platelet count
- Bleeding time (BT)
- Platelet function analysis (PFA)
Secondary Hemostasis
- Partial thromboplastin time (PTT)
- Prothrombin time (PT)
- Mixing Study
- Clotting Factors
Laboratory Coagulation Tests - Primary Hemostasis - Platelet Count
- Normal range 150K - 400K/uL
- False lows: platelet clumps/ fibrin strands (traumatic draw)
Laboratory Coagulation Tests - Primary Hemostasis - Bleeding Time
Not standardized
Laboratory Coagulation Tests - Primary Hemostasis - Platelet Function Analysis (PFA)
- Stimulates in vivo condition - high shear stress
- Utilizes platelet agonists (collagen/ADP and collagen/EPI) to interrogate platelet function
- Has replaced bleeding time in many institutions because more standardized
Interpretation:
- Normal A and E: normal
- Normal A, prolonged E: drug effect (ASA)
- Both prolonged: vWD
- Both prolonged: platelet abnormality
Laboratory Coagulation Tests - Secondary Hemostasis - Partial Thromboplastin Time (PTT)
- Kaolin + cephalin + Ca2+ + patient plasma
- Intrinsic and common pathway: VIII, IX, XI, XII; II, V, X, XII, Fibrinogen
Laboratory Coagulation Tests - Secondary Hemostasis - Prothrombin Time (PT)
- Tissue thrombplastin + Ca2+ + patient plasma
- Extrinsic and common pathway: VII; II, V, X, XIII, Fibrinogen
Laboratory Coagulation Tests - Secondary Hemostasis - Mixing Study
- Patient sera + pooled sera: check PTT (or PT)
- If PTT normal (corrects) then FACTOR DEFICIENCY
- If PTT abnormal (no correction) then INHIBITOR PRESENT
Laboratory Coagulation Tests - Secondary Hemostasis - Clotting Factors
- Known specific factor-poor plasma + Patient plasma
- Run either PT or PTT depending on which factor being evaluated
Abnormalities of the Vessel Wall - Clinical Picture
- Petechiae
- Purpura
Abnormalities of the Vessel Wall - Coagulation Test Results
Normal
Abnormalities of the Vessel Wall - Etiologies
- Drugs
- Impaired Collagen Support
- Henoch-Schonlein Purpura
- Hereditary Hemorrhagic Telangiectasia
- Amyloid Infiltration
- DIC
Abnormalities of the Vessel Wall - Etiologies - Drugs
Drug-induced immune complexes deposit in the vascular wall leading to leukocytoclastic vasculitis
Abnormalities of the Vessel Wall - Etiologies - Impaired Collagen Support
- SCURVY: vitamin C deficiency, required for hydroxylation of procollagens
- EHLERS-DANLOS SYNDROME: inherited collagen abnormalitiy
- Elderly
- CUSHING SYNDROME: excessive steroids = protein wasting = loss of vascular support
Abnormalities of the Vessel Wall - Etiologies - Henoch-Schonlein Purpura
- Systemic hypersensitivity disease in which circulating immune complexes deposit in the vessels
- Unknown etiology
- Colicky abdominal pain, polyarthralgias, acute glomerulonephritis
Abnormalities of the Vessel Wall - Etiologies - Hereditary Hemorrhagic Telangiectasia
- AD
- Dilated tortuous vessels within thin walls
Abnormalities of the Vessel Wall - Etiologies - Amyloid Infiltration
Weakens vessel walls
Thrombocytopenia - Clinical Findings
- Normal platelet count: 150,000 - 400,000
- Typically not a problem until count
Thrombocytopenia - Coagulation Test Results
- Platelet count decreased
- BT and PFA prolonged if platelet
Thrombocytopenia - Etiologies
Decreased Production (bone marrow)
- Neoplastic
- Non-neoplastic
Increased Peripheral Destruction/Sequestration
- Non-immune
- Allo-immune Condition
- Auto-immune Conditions (immune thrombocytopenia purpura, heparin induced thrombocytopenia, HIV associated, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome)
- Dilutional Effect secondary to Massive Transfusions
Thrombocytopenia - Etiologies - Decreased Bone Production - Neopastic
- Non-hematopoietic neoplasms infiltrating marrow (prostate, breast, neuroblastoma, etc.)
- Hematopoietic neoplasms (AML, ALL, MDS, lymphoma, etc.)
Thrombocytopenia - Etiologies - Decreased Bone Production - Non-neoplastic
- Infections
- Drugs
- EtOH, toxins
- B12/Folate deficiency
Thrombocytopenia - Etiologies - Increased Peripheral Destruction/ Sequestration - Non-immune
- SEQUESTRATION: splenomegaly (hypersplenism)
- MECHANICAL DAMAGE: prosthetic heart valves, malignant hypertension
Thrombocytopenia - Etiologies - Increased Peripheral Destruction/ Sequestration - Allo-immune Condition
- One person develops antibodies to platelets after being to platelets of another person
- Rare because most people ave similar platelet antigens
- May cross placenta causing fetal thrombocytopenia
Thrombocytopenia - Etiologies - Increased Peripheral Destruction/ Sequestration - Auto-immune Conditions - Immune Thrombocytopenia Purpura (ITP)
- Primary (idiopathic autoimmune platelet destruction vs Secondary (identifiable etiology causing autoimmune platelet destruction)
Chronic ITP
- Adults
- Insidious onset of symptoms
- Secondary etiologies include SLE, HIV, drugs and other viruses
- Peripheral blood shows thrombocytopenia with giant platelets reflected by INCREASED MPV
- IgG autoAb against platelet antigens (Gp IIb-IIIa or Gp Ib-IX)
- Abs bind to platelets, platelets are then opsonized and removed by reticuloendothelial system (spleen)
- Spleen - NORMAL SIZE; congestion of sinusoids, macrophages, splenic follicular hyperplasia, occasional megakaryocytic
- Bone marrow examination done only if patient not responsive to therapy to exclude other etiologies of thrombocytopenia; shows INCREASED NUMBERS OF MEGAKARYOCYTES with left shifted maturation
- TREATMENT: immunosuppression with steroids; splenectomy, IVIG, rituximab (CD20 antibody)
Acute ITP
- Kids
- Abrupt onset of thrombocytopenia
- Preceded by viral illnesses (2 weeks)
- Self limited, resolves in 6 months
- 20% of kids will persist beyond 6 months (chronic ITP similar to adults)
Thrombocytopenia - Etiologies - Increased Peripheral Destruction/ Sequestration - Auto-immune Conditions - Heparin Induced Thrombocytopenia (HIT)
Type I
- Most common; due to direct platelet aggregation caused by heparin
- Moderate thrombocytopenia
- Occurs within a few days of heparin
- Clinically insignificant
Type II
- 5-14 days after heparin is started or sooner if patient has been previously sensitized with heparin
- Moderate to severe drop in platelets
- Antibodies directed against heparin-platelet factor 4 complex results in direct platelet activation
- Paradoxical thrombosis due to platelet activation
- LIFE THREATENING - MUST DISCONTINUE HEPARIN
- If patient has history of HIT lovenox (LMW heparin) is also contraindicated
- BUT risk of developing HIT is less with LMW heparin
Thrombocytopenia - Etiologies - Increased Peripheral Destruction/ Sequestration - Auto-immune Conditions - HIV Associated
- Common problem
- CD4 is present on surface of megakaryocytic
- Direct infection of megakaryoctes by HIV
- HIV results in dysregulation and hyperplasia of B cells
- Autoantibody production towards platelet Gp IIb-IIIa
Thrombocytopenia - Etiologies - Increased Peripheral Destruction/ Sequestration - Auto-immune Conditions - Thrombotic Thrombocytopenia Purpura (TTP)
Classic pentad of clinical findings
- Fever
- Thrombocytopenia
- Microangiopathic hemolytic anemia (dx: schistocytes, increase LDH, indirect hyperbilirubinmemia)
- Neurologic symptoms: seizures, altered mental status, hemiplegia, parasthesias, visual defects, aphasia
- Renal failure
Hyaline thrombi (platelet aggregates) formation
- Platelet consumption = thrombocytopenia
- Red cell trapping in microthrombi = microangiopathic hemolytic anemia (schistocytes)
- Organ dysfunction
ADAMTS 13 Deficiency
- Normally: ADAMS 13 degrades HMW multimers of vMF
- DEFICIENCY: accumulation of of HMW multimers which can promote platelet aggregation
- ACQUIRED: autoantibody against ADAMTS 13
- INHERITED: inactivating mutation in gene
- Endothelial cell injury can exacerbate
Treatment of TTP is total plasma exchange to remove autoantibody and replenish normal levels of ADAMTS 13
- Platelet transfusions are CONTRAINDICATED - worsen the thrombi
Thrombocytopenia - Etiologies - Increased Peripheral Destruction/ Sequestration - Auto-immune Conditions - Hemolytic Uremic Syndrome
- Presents with bloody diarrhea and subsequent renal failure
- Often associated with E. coli strain 0157 - H7
- Occurs more in kids
- HUS patient have normal levels of ADAMTS 13 enzyme
- Treatment is supportive care, value of plasma exchange is unclear
Platelet Function Abnormalities - Clinical Findings
Prolonged bleeding after cuts/trauma
Platelet Function Abnormalities - Coagulation Test Results
- PT, PTT, platelet count normal
- PFA - abnormal
- Platelet aggregation studies: examines the functionality of platelets when stimulated with various agonists: collagen, ADP, eli, thrombin, ristocetin
Platelet Function Abnormalities - Etiology
Acquired
- Drugs: ASA, NSAIDs, many others
- Uremia: unknown pathogenesis
Congenital
- Platelet adhesion defect: Bernard-Soulier
- Platelet aggregation defect: Glanzmann’s Thrombasthenia
Platelet Function Abnormalities - Etiology - Congenital - Bernard-Soulier
- AR
- Deficient platelet Gp Ib-IX complex where vWF needs to bind
- vWF linkes platelets to endothelium
- Giant platelets
- Platelet aggregation: EVERYTHING WORKS BUT RISTOCETIN
Platelet Function Abnormalities - Etiology - Congenital - Glanzmann’s Thrombasthenia
- AR
- Deficient Gp IIb-IIIa which is the place where fibrinogen cross links between platelets
- Platelet aggregation: NOTHING WORKS BUT RISTOCETIN
Clotting Factor Abnormalities - Clinical Findings
- Prolonged bleeding after laceration, surgery or trauma
- Bleeding into GI/GU tract
- Bleeding into weight bearing joints
Clotting Factor Abnormalities - Coagulation Test Results
Depends on which factor is deficient
Clotting Factor Abnormalities - Etiologies
- von Willebrand Disease
- Factor VIII Deficiency (Hemophilia A)
- Factor IX Deficiency (Hemophilia B, Christmas Disease)
- Acquired Deficiencies
Clotting Factor Abnormalities - Etiologies - von Willebrand Disease
- Prolonged bleeding from cuts, menorrhagia, mucous membrane bleeding
- Abnormal PFA and PTT; normal platelet count
- AD usually; 1% of population
- Different subtypes with severity of symptoms dependent on which subtype
Type I (70%) - QUANTITATIVE decrease in vWF -
Clotting Factor Abnormalities - Etiologies - Factor VIII Deficiency (Hemophilia A)
- VIII is the cofactor for IX
- X linked recessive
- Males and homozygous females
- Heterozygous females can be symptomatic due to unfavorable LYONIZATION
- 30% of families have no family history - new mutations
- ## Clinical symptoms correlate with VIII level
Clotting Factor Abnormalities - Etiologies - Factor VIII Deficiency (Hemophilia A) - Symptoms
- Easy bruising, massive hemorrhage after surgery/trauma
- Spontaneous hemorrhage into large joints = hemarthroses
- NO mucous membrane bleeding or petechiae
Clotting Factor Abnormalities - Etiologies - Factor VIII Deficiency (Hemophilia A) - Diagnosis
- Prolonged PTT
- Normal PFA, platelet count, PT
- Factor VIII assay (functional)
Clotting Factor Abnormalities - Etiologies - Factor VIII Deficiency (Hemophilia A) - Treatment
- Humate P (purified, plasma derived) or recombinant (Kogenate)
- Purified and recombinant VIII virtually eliminates infectious risk
- Inhibitor development is still a risk of replacement therapy
Clotting Factor Abnormalities - Etiologies - Factor VIII Deficiency (Hemophilia A) - Why do symptoms occur if only one arm of cascade is knocked out?
- Tests may not reflect true, in vivo reality
- Fibrin formation/deposition is inadequate to maintain clot (extrinsic role is the burst to get the cascade moving; intrinsic pathway maintains it)
- Inappropriate fibrinolysis (high levels of thrombin needed to activate TAFI (inhibits fibrinolysis); this does not occur with only one pathway working
Clotting Factor Abnormalities - Etiologies - Factor IX Deficiency (Hemophilia B)
- Clinically identical to Factor VIII deficiency (remember, VIII and IX work together to activate X)
- X linked recessive with variable clinical severity
- 14% of patients have normal levels of IX, BUT ABNORMAL FUNCTION
- DIAGNOSIS: prolonged PTT; normal PT, PFA, platelet count; factor IX assay (functional)
- TREATMENT: recombinant factor IX
Clotting Factor Abnormalities - Acquired Deficiencies
Vitamin K Deficiency
- II, VII, IX, X, protein C
- This is how Coumadin works
Liver disease
- Majority of coagulation cascade proteins are made in the liver
DIC
Disseminated Intravascular Coagulation
Not a primary disease - rather is a physiologic consequence of other disease
- Thrombohemorrhagic disorder
- Pathologic activation of the coagulation cascade systemically in the microvasculature
- Signs/symptoms related to tissue hypoxia and infarction and/or hemorrhage due to consumption of coagulation factors
Disseminated Intravascular Coagulation - Coagulation Tests
- Prolonged PT, PTT
- Decreased platelet
- Decreasing fibrinogen
- Increased d-dimer
Disseminated Intravascular Coagulation - Etiologies
Obstetric Complications
- Placental abruption
- Retained products of conception
- Septic abortion
Infections
- Gram negative sepsis
- Meningococcemia
Neoplasms
- APL (AML-M3)
- Adenocarcinoma
Massive Tissue Injury
Disseminated Intravascular Coagulation - Mechanisms
Tissue factor release into the blood
- Obstetric complications
- Substance released by blasts of APL
- MUCIN of adenocarcinoma released into blood directly activating X
- Gram negative sepsis with bacterial endotoxins result in release of IL-1 and TNF which increase the TF on endothelial cells
Wide spread endothelial cell injury
- Infectious etiologies via TNF production (increases leukocyte adhesion and free radical formation which damages endothelium)
- Antigen/antibody complex deposition (SLE)
- Heat stroke, burns
Disseminated Intravascular Coagulation - Consequences
Widespread fibrin deposition in microvasculature
- Ischemia of associated organs (ischemic bowel, renal failure, hepatic necrosis, skin/digit necrosis)
- Hemolytic anemia (microangiopathic; schistocytes on smear)
Hemorrhagic diathesis
- Factor and platelet consumption faster than production
- Plasminogen activation (fibrinolysis in increased d-dimer/FDPs which inhibit platelet aggregation and have antithrombin activity)
Disseminated Intravascular Coagulation - Morphology
- Thrombi in brain, heart, lungs, kidneys, adrenals, spleen and liver
- CNS micro-infarcts/hemorrhage with associated symptoms
- Waterhouse-Friderichsen Syndrome (massive bilateral adrenal hemorrhage associated with meningococcus)
- Sheehan Syndrome - postpartum pituitary necrosis
- Toxemia of pregnancy - microthrombi in placenta
Disseminated Intravascular Coagulation - Clinical Course and Prognosis
Acute, fulminent - typically present with bleeding
- Endotoxic shock, trauma
- Obstetric complications
- APL
Chronic, insidious - typically presents with thrombosis
- Carcinomatosis
Presentation
- Microangiopathic hemolytic anemia
- Dyspnea, cyanosis, respiratory failure
- Convulsions, coma
- Oliguria, acute renal failure
- Circulatory shock
Disseminated Intravascular Coagulation - Coagulation Findings
- Decreased platelets
- Prolonged PT and PTT
- Decreasing fibrinogen
- Peripheral smear
Peripheral smear
- Schistocytes with compensatory increase in reticulocytes/nRBS’s if marrow stores available
- Leukocytosis and neutrophilia, sometimes with LEFT SHIFT; toxic changes
- Decreased numbers of platelets; giant platelets
Disseminated Intravascular Coagulation - Treatment
- Treat underlying problem/illness
- Supportive care
