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Vascular Abnormalities

• Disorders of the microcirculation, platelets, or plasma proteins can lead to abnormal bleeding, known as purpura.
• Petechiae appear as small, purplish hemorrhagic spots on the skin or mucous membranes.
• Ecchymosis refers to larger patches of bleeding in the tissues.

Types of Vascular Conditions

• Mechanical force can cause vascular conditions.
• Genetic structural malformation can cause vascular conditions.
• Inflammation and obstructions in blood vessels can cause vascular conditions.
• Disorders of perivascular tissue can cause vascular conditions.
• Miscellaneous causes such as infection, skin disease, and psychogenic reasons can cause vascular conditions.

Blood Vessel Malformation

• Hereditary Hemorrhagic Telangiectasia (HHT), also known as Osler-Weber-Rendu disease, is a type of blood vessel malformation.
• HHT results from genetic mutations.
• HHT is inherited as an autosomal dominant trait.
• HHT involves a reduced amount of functional proteins in the tissue lining of blood vessels.
• HHT results in skin and mucous membrane-associated epistaxis (nosebleeds) and other bleeding conditions.
• ENG, ACVRL1, and SMAD4 genes interact with growth factors that control blood vessel development.
• Type 1 HHT is associated with the ENG gene.
• Type 2 HHT is associated with the ACVRL1 gene.
• The cause of Type 3 HHT is unknown.
• Juvenile polyposis/HHT syndrome is caused by mutations in the SMAD4 gene.

Other Vasculopathies

• Multiple Myeloma and Systemic Amyloidosis can lead to other vasculopathies.
• Moyamoya disease can lead to other vasculopathies.
• Cerebral small vessel disease can lead to other vasculopathies.

Vasculitis

• ANCA, or Anti-neutrophil Cytoplasmic Antibody-Positive Vasculitis, is a type of vasculitis.
• Cryoglobulinemia is a type of vasculitis.
• Hypergammaglobulinemic purpura is a type of vasculitis.
• HSP, or Henoch-Schönlein purpura is a type of vasculitis.

Anti-neutrophil Cytoplasmic Antibody – Positive Vasculitis (ANCA)

• ANCA includes c-ANCA and p-ANCA.
• ANCA is observed in SLE (Systemic Lupus Erythematosus) and Wegener's granulomatosis.
• ANCA serves as serologic markers of primary necrotizing systemic vasculitis.

Cryoglobulinemia

• Cryoglobulin immune deposits precipitate in dermal vessels.
• 90% of patients with Waldenström's primary macroglobulinemia (WM) have MYD88 L265P mutations.
• The symptoms of Cryoglobulinemia are cutaneous infarcts and petechiae.
• Platelet count is usually normal, though patients may experience chronic anemia and bleeding episodes.
• Bleeding caused by abnormalities in platelet adhesiveness and prothrombin time (PT) can be seen, along with low factor VIII values.
• It can cause increased intraluminal pressure.

Hypergammaglobulinemic Purpura

• Hypergammaglobulinemic purpura is characterized by polyclonal hypergammaglobulinemia.
• Autoimmune disorders like Sjögren's syndrome, SLE, and chronic hepatitis C are secondary forms of Hypergammaglobulinemic purpura.

Henoch-Schönlein Purpura

• Henoch-Schönlein Purpura (HSP) primarily occurs in children between 4 and 11 years old.
• Reddish-purple spots, resembling bruises, are a distinctive sign of HSP.
• HSP is an acute immunoglobulin A (IgA)-mediated disorder characterized by generalized vasculitis involving small vessels of the skin, gastrointestinal tract, kidneys, joints, and, rarely, the lungs and central nervous system.

Vascular Obstruction

• Vascular abnormalities that can cause bleeding disorders depend on the type of abnormality.
• Thrombus, which includes blood clots, can cause disseminated intravascular coagulation.
• Emboli include septic emboli, which produce endocarditis, and thromboemboli, which produce atrial fibrillation.
• Other occlusions may include immunoglobulins, which will produce Multiple myeloma and Waldenström's primary macroglobulinemia.
• Other occlusions may include plasma proteins which can generate cryoglobulinemia.
• Other occlusions may include Fibrin, which generates Cryofibrinogenemia
• Other occlusions may include red blood cells, which produce polycythemia.
• Other occlusions may include platelets, which cause thrombocytosis.
• Other occlusions may include fat, which forms a fat emboli syndrome.

DIC - Disseminated Intravascular Coagulation

• DIC may be initiated by a number of factors:
• Vascular damage exposure of collagen
• Activation of XII
• DIC is characterized by excess thrombin formation, conversion of fibrinogen to fibrin, and consumption platelet deposition and consumption
• It is also characterized by both thrombosis and hemolysis

Cryofibrinogenemia

• Cryofibrinogen are cold precipitable plasma proteins.
• Lesions in associated cryofibrinogen disorders, like Raynaud's phenomenon, develop as the result of fibrin thrombi obstructing small- to medium-sized dermal blood vessels.

Septic Emboli

• Results from the development of tissue ischemia and necrosis of the skin and subcutaneous fate, and occasionally deeper tissues.
• Septic Emboli is associated with patients who have end-stage renal failure and undergoing hemodialysis

Bleeding because of Perivascular Tissue

• Ehlers-Danlos syndrome (EDS) causes bleeding by weakening perivascular tissue
• Marfan's syndrome causes bleeding by weakening perivascular tissue
• Loeys-Dietz syndrome causes bleeding by weakening perivascular tissue
• Osteogenesis imperfecta causes bleeding by weakening perivascular tissue
• Pseudoxanthoma elasticum causes bleeding by weakening perivascular tissue
• Scurvy causes bleeding by weakening perivascular tissue
• Steroid-induced purpura causes bleeding by weakening perivascular tissue
• Solar purpura (senile purpura) causes bleeding by weakening perivascular tissue

Ehlers-Danlos Syndrome (EDS)

• EDS is caused by abnormalities of collagen synthesis or processing.
• It defect in type 3 collagen, which is particularly abundant in the arterial wall and intestine.
• Can cause excessive bleeding
• Type IV EDS is prone to arterial aneurysms and dissections, with significant bleeding from spontaneous rupture of medium-sized abdominal arteries, and intestinal rupture.
• EDS IV is caused by structural defects in the proa1(III) chain of collagen type III encoded by COL3A1, and is inherited in an autosomal dominant pattern

Pseudoxanthoma Elasticum (PXE)

• Also called Gröenblad - Strandberg syndrome, or Grönblad -Strandberg syndrome.
• PXE is an inherited connective tissue disorder that results in calcification and mineralization of elastic fibers, especially in the internal elastic lamina of medium-sized arteries with subsequent rupture of the blood vessel.
• It follows an autosomal recessive inheritance pattern
• PXE is caused by ABC-C6 gene mutations that resultin nonfunctional MRP6 protein

Scurvy

• Deficiency of vitamin C weakens collagen strands due to abnormal triple helical structures.
• Abnormal collagen results in defective perivascular supportive tissues, predisposing a patient to capillary fragility, delayed wound healing, petechiae and purpura.

Solar Purpura (Senile Purpura)

• Solar Purpura is caused by degradation of collagen and elastin

Purpura Associated with Infections

• Acute febrile illnesses with petechiae
• Rickettsial diseases include purpura associated with infections.
• Brazilian purpura fever
• Rat bite fever
• Hemorrhagic fever
• Vibrio vulnificus infection
• Strongyloides infection
• Bacterial toxin produce deendothelialization induced by an endotoxin

Purpura Related to Miscellaneous Causes

• Contact dermatitis can cause purpura
• Steroid use can cause purpura
• Drug reactions can cause purpura
• Vascular malignancy (Kaposi sarcoma, vascular tumors)
• Purpura simplex occurs in 30% of women
• Factitious or self-imposed purpura
• Religious stigmata

Quantitative Platelet Disorders

• Thrombocytopenia is a platelet disorder
• Thrombocytosis is a platelets disorder

Thrombocytopenia

• Thrombocytopenia involves deficient platelet counts

Major Categories of Thrombocytopenic Conditions

• Disorders of production can lead to this condition.
• Disorders of destruction or utilization can lead to thrombocytopenic conditions.
• Disorders of platelet distribution and dilution can lead to thrombocytopenic conditions.

Disorders of Production

• These are caused by hypoproliferation of the megakaryocytic cell line or ineffective thrombopoiesis due to acquired conditions or hereditary factors.
• Can result from acquired damage to hematopoietic cells of the bone marrow caused by irradiation, drugs (e.g., chloramphenicol, chemotherapeutic agents), chemicals (e.g., insecticides), and alcohol.

Disorders of Destruction or Utilization

• Destructions caused by immune mechanisms, Antigens, Antibodies, or Complement
• Posttransfusion purpura
• Drugs
• Bacterial sepsis
• Immune thrombocytopenia
• Isoimmune Neonatal Thrombocytopenia
• Thrombocytopenia in pregnancy

Heparin-Induced Thrombocytopenia (HIT)

• HIT is characterized by the development of Thrombocytopenia as a result of heparin treatment.
• HIT can be divided into two types: type I is nonimmune, and type II is immune.

Nonimmune HIT

• Nonimmune HIT is benign and affects roughly 10% of patients receiving heparin anticoagulant therapy.
• Platelet count is >100,000/μL, however, a rapid decline is observed within the first 2 days of heparin administration.
• The platelet count returns to normal levels within 5 days despite continued heparin use or within 2 days if heparin therapy is discontinued.
• The mechanism of action is direct interaction between heparin and platelets

Immune HIT

• Platelet count range falls between 20,000 to 150,000/μL.
• The lowest count is reached around 5 days after the platelet decline begins.
• Platelet count will begin to rise approximately 2 days after discontinuation of heparin therapy, then returns to normal within 4-10 days after the heparin is discontinued.

Pathophysiology of HIT

• Immune HIT is caused by an antibody that recognizes heparin bound to PF4 on the platelet surface.
• The antibody binds to the heparin-PF4 complex, allowing it to attach to the Fc receptor on the platelet.
• The interaction with the Fc receptor activates the platelet which results to platelet aggragation, and thrombocytopenia.

Laboratory Data of HIT

• Enzyme-linked immunosorbent assay (ELISA) is used to detect HIT markers.
• Platelet aggregation is another means of detection of HIT markers.
• Serotonin release is another means of detection of HIT markers.

Increased Utilization of Platelets

• Immune Thrombocytopenic Purpura is the increased utilization of platelets
• Idiopathic Thrombocytopenic Purpura is an acquired immune-mediated disorder characterized by isolated thrombocytopenia - platelet count less than 100 × 10°/L and absence of an underlying cause.
• ITP is marked by normal bone marrow, low platelet count, and no other definable causes of thrombocytopenia

Characteristics of Immune Thrombocytopenia

• Peak age Newly Diagnosed - 2-5 years
• Chronic peak onset: Adulthood (30-60 years)
• Common Newly Diagnosed - History of infection
• Chronic, history of infection - Uncommon
• Newly Diagnosed Spontaneous remission: Common
• Chronic Spontaneous remission: Rare

Epidemiology of ITP

• ITP is commonly a benign illness in the pediatric population.
• ITP can be classified by duration into newly diagnosed, persistent (3- 12 months duration), and chronic (≥12 months).
• Adults - chronic
• Children - acute
• ITP is most common in young women (approximately 70% of patients are 10 to 40 years old).
• Chronic ITP is a destructive thrombocytopenia caused by an autoantibody.

Clinical Signs and Symptoms of ITP

• Purpura is a clinical sign and symptom of ITP.
• Epistaxis is a clinical sign and symptom of ITP.
• Gingival bleeding is a clinical sign and symptom of ITP.
• Hematuria is a clinical sign and symptom of ITP.
• GI bleeding is a clinical sign and symptom of ITP.
• Intracerebral hemorrhage is a clinical sign and symptom of ITP.

Pathophysiology of ITP

• Two new concepts of ITP are:
• The same antibodies that mediate platelet destruction also mediate impaired platelet production by damaging megakaryocytes and/or blocking their ability to release pro-platelets where T-cell – mediated effects are believed to play a role.
• Ten to twenty percent of cases are not antibody mediated in ITP

Types of ITP

• Acute ITP affects 2 - 6 y/o children who have just recovered from a viral illness
• Chronic ITP affects 20 – 50 y/o adults who produce an IgG antibody that coats the platelets, and platelets are sequestered and destroyed in spleen

Laboratory Data of ITP

• ASH guidelines in the diagnosis:
• Presence of thrombocytopenia, as well as an absence of anemia unless hemorrhage has occurred, and lack of cell abnormalities
• Lack of alternative causes of thrombocytopenias
• Absence of infections

Treatment of ITP

• intravenous immunoglobulin (IVIg or WinRho, anti-D immune globulin)
• Splenectomy can be performed as an option for therapy.
• Platelet transfusion can be performed as an option for therapy.

Increased Utilization of Platelets

• Intravascular coagulation contributes to increased utilization
• Vascular injury or occlusion contributes to increased utilization
• Tissue injury contributes to increased utilization
• Trauma contributes to increased utilization
• Obstetrical complications contributes to increased utilization
• Microbial sepsis contributes to increased utilization

Thrombotic Thrombocytopenic Purpura

• Thrombotic Thrombocytopenic Purpura (TTP)is a clinical syndrome with a high mortality rate that is characterized by formation of microthrombi in the microvasculature
• Characterized by profound thrombocytopenia.
• Characterized by microangiopathic hemolytic anemia.
• Characterized by Fever
• Characterized by Neurologic symptoms like headache and stroke, as well as issues with the renal system

Types of TTP

• Idiopathic – linked to enzyme ADAMTS13 (a disintegrin-like and metalloprotease domain with thrombospondin-type motifs), responsible or the breakdown of large von Willebrand factor (vWF) multimers.
• Secondary - diagnosed in patients with history of medications; HIV, autoimmune disorders, allogeneic bone marrow transplant.
• Hereditary (Upshaw-Schulman) - result of inheritance of a deficiency of ADAMTS13

Disorders of Platelet Distribution and Dilution

• Result from a pooling of platelets in the spleen that occurs frequently when splenomegaly is present, like Gaucher's disease.
• This type of thrombocytopenia develops when more than a double or triple increase in platelet production is required to maintain a normal count of circulating platelets.
• Disorders that can lead to splenic abnormalities like cirrhosis or posthepatic cirrhosis, lymphomas, and leukemias.

Posttransfusion Thrombocytopenia

• May develop due to massive blood transfusion of units of packed RBC and plasma expanders resulting in a reduced platelet count, dilutional thrombocytopenia.

Hereditary Defects of Platelet Function with Thrombocytopenia

• Include Fanconi's syndrome, constitutional aplastic anemia and its variants, ameiosis thrombocytopenia (TAR syndrome), X-linked amegakaryocytic thrombocytopenia, WAS, May-Hegglin anomaly, and Hereditary macrothrombocytopenia

• Platelet morphology must be observed when examining a peripheral blood smear; abnormal variation in size must be noted.

• Disorders of platelet size are as follows:

1. In WAS, which is a condition that leads to the smallest platelets
2. May-Hegglin anomaly: leads to the presence of large platelets and the presence of Döhle-like bodies in the granulocytic leukocytes.
3. Alport syndrome exhibits giant platelets and thrombocytopenia
4. Bernard-Soulier Syndrome (BSS) demonstrates the largest platelets

Wiskott-Aldrich Syndrome (WAS)

• Patients are Susceptible to infections and have problems with abnormal bleeding
• The platelets do not form blood clots well because they are unusually small, dysfunctional platelets.

Etiology of WAS

• The defective gene which codes for WASp protein is located on the short arm of the X chromosome
• The Wiskott-Aldrich syndrome protein assists for the production of a protein that relay signals from outside of lymphocytes to the actin cytoskeleton for movement, adhesion, and signal transduction to the nucleus.

Signs and Symptoms of WAS

• Thrombocytopenic purpura is a sign and symptom

• Increased susceptibility to bacterial, viral, and fungal infections

• Eczema of the skin is a sign and symptom

• Autoimmune manifestations include hemolytic anemia or idiopathic thrombocytopenic purpura caused by self-reactive antibodies along with vasculitis

• WAS causes an increased risk of cancer

• Lymphomas or leukemias that arise from B lymphocytes are the most common.

• Non-Hodgkin's lymphoma makes up the majority of cases.

• Lab tests could test for WAS with:

• Sequencing the WAS gene

• Determining the presence of WASp protein in red blood cells

MYH9-Related Thrombocytopenia Syndromes (May-Hegglin Anomaly)

• Are Autosomal Dominant Macrothrombocytopenia syndromes (May-Hegglin Anomaly)
• Consists of Sebastian, Fechtner, and Epstein syndromes
• Are Other Inherited thrombocytopenia that have common mutations with MYH9, a platelet cytoskeletal contractile protein

Pathophysiology of MYH9 Translocation

• Often autosomal dominant, some have an X-linked or recessive inheritance
• Several mutations in the MYH9 gene lead to premature release of platelets from the bone marrow, macrothrombocytopenia, and cytoplasmic inclusion bodies within leukocytes.
• The MYH9 gene encodes NMMHC-IIA consists of 40 exons and is located on chromosome 22q12–13.50.
• Up to date, 31 mutations in 11 different exons have been described.

Clinical Signs and Symptoms of May-Hegglin Anomaly

• Abnormal bleeding tendencies are usually moderate, menorrhagia and easy bruising are most frequent

• The hemostatic defect is unclear, but is proportionate to the degree of thrombocytopenia

• Lab findings include:

• Presence of macrothrombocytopenia

• Abnormally large and poorly granulated platelets and thrombocytopenia coexist

• Döhle body-like inclusions in neutrophils, eosinophils, and monocytes

• Compare it to chronic autoimmune thrombocytopenia, which is a condition, to evaluate platelet size using the blood film, platelet size histogram, and (calculated) MPV.

• It should be detected by the best marker, which is the detection, by immunostaining, of NMM-lla clusters.

• Platelet aggregation is useful for detecting these anomalies

• A diagnostic workup for MYH9 cases should also include exclusion of iron deficiency anemia and ophthalmologic screening and renal function assessment.