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Abnormal bleeding

MedGen UID:
264316
Concept ID:
C1458140
Pathologic Function
Synonyms: Bleeding diathesis; Bleeding tendencies; Bleeding tendency
SNOMED CT: Tendency to bleed (248250000); Bleeding diathesis (64779008); Bleeding tendency (64779008); Bleeding disorder (64779008)
 
HPO: HP:0001892

Definition

An abnormal susceptibility to bleeding, often referred to as a bleeding diathesis. A bleeding diathesis may be related to vascular, platelet and coagulation defects. [from HPO]

Conditions with this feature

Bernard Soulier syndrome
MedGen UID:
2212
Concept ID:
C0005129
Disease or Syndrome
Bernard-Soulier syndrome is an autosomal recessive bleeding disorder caused by a defect in or deficiency of the platelet membrane von Willebrand factor (VWF; 613160) receptor complex, glycoprotein Ib (GP Ib). GP Ib is composed of 4 subunits encoded by 4 separate genes: GP1BA, GP1BB, GP9, and GP5 (173511). Genetic Heterogeneity of Platelet-Type Bleeding Disorders Inherited platelet disorders are a heterogeneous group of bleeding disorders affecting platelet number, function, or both. Functional defects can involve platelet receptors, signaling pathways, cytoskeletal proteins, granule contents, activation, or aggregation (review by Cox et al., 2011 and Nurden and Nurden, 2011). Platelet-type bleeding disorders include Bernard-Soulier syndrome (BDPLT1); Glanzmann thrombasthenia (BDPLT2; 273800), caused by mutation in the ITGA2B (607759) or ITGB3 (173470) gene; pseudo-von Willebrand disease (BDPLT3; 177820), caused by mutation in the GP1BA gene (606672); gray platelet syndrome (BDPLT4; 139090), caused by mutation in the NBEAL2 gene (614169); Quebec platelet disorder (BDPLT5; 601709), caused by tandem duplication of the PLAU gene (191840); May-Hegglin anomaly (BDPLT6; 155100), caused by mutation in the MYH9 gene (160775); Scott syndrome (BDPLT7; 262890), caused by mutation in the TMEM16F gene (608663); BDPLT8 (609821), caused by mutation in the P2RY12 gene (600515); BDPLT9 (614200), associated with deficiency of the glycoprotein Ia/IIa receptor (see ITGA2; 192974); glycoprotein IV deficiency (BDPLT10; 608404), caused by mutation in the CD36 gene (173510); BDPLT11 (614201), caused by mutation in the GP6 gene (605546); BDPLT12 (605735), associated with a deficiency of platelet COX1 (176805); susceptibility to BDPLT13 (614009), caused by mutation in the TBXA2R gene (188070); BDPLT14 (614158), associated with deficiency of thromboxane synthetase (TBXAS1; 274180); BDPLT15 (615193), caused by mutation in the ACTN1 gene (102575); BDPLT16 (187800), caused by mutation in the ITGA2B (607759) or ITGB3 (173470) gene; BDPLT17 (187900), caused by mutation in the GFI1B gene (604383); BDPLT18 (615888), caused by mutation in the RASGRP2 gene (605577); BDPLT19 (616176), caused by mutation in the PRKACG gene (176893); BDPLT20 (616913), caused by mutation in the SLFN14 gene (614958); BDPLT21 (617443), caused by mutation in the FLI1 gene (193067); BDPLT22 (618462), caused by mutation in the EPHB2 gene (600997); BDPLT23 (619267), caused by mutation in the ITGB3 gene (173470); BDPLT24 (619271), caused by mutation in the ITGB3 gene (173470); and BDPLT25 (620486), caused by mutation in the TPM4 gene (600317). See reviews by Rao (2003), Cox et al. (2011), and Nurden and Nurden (2011). For a discussion of the genetic heterogeneity of hereditary thrombocytopenia, see THC1 (313900).
Congenital factor V deficiency
MedGen UID:
4633
Concept ID:
C0015499
Disease or Syndrome
Factor V deficiency is a rare autosomal recessive bleeding disorder with variable phenotypic expression (summary by van Wijk et al., 2001).
Hereditary factor XI deficiency disease
MedGen UID:
8770
Concept ID:
C0015523
Disease or Syndrome
Factor XI deficiency is an autosomal bleeding disorder characterized by reduced levels of factor XI in plasma (less than 15 IU/dL). Bleeding occurs mainly after trauma or surgery. On the basis of the concordance or discordance of F11 antigen and activity, the disorder is classified into the more frequent cross-reactive negative (CRM-) and the rarer CRM positive (CRM+) (summary by Duga and Salomon, 2009).
Hereditary factor VIII deficiency disease
MedGen UID:
5501
Concept ID:
C0019069
Disease or Syndrome
Hemophilia A is characterized by deficiency in factor VIII clotting activity that results in prolonged oozing after injuries, tooth extractions, or surgery, and delayed or recurrent bleeding prior to complete wound healing. The age of diagnosis and frequency of bleeding episodes are related to the level of factor VIII clotting activity. Individuals with severe hemophilia A are usually diagnosed during the first two years of life following oral or soft tissue bleeding either with procedures or due to a known family history of hemophilia. Without prophylactic treatment, individuals may average up to two to five spontaneous bleeding episodes each month including spontaneous joint bleeds or deep-muscle hematomas, and prolonged bleeding or excessive pain and swelling from minor injuries, surgery, and tooth extractions. Individuals with moderate hemophilia A seldom have spontaneous bleeding, although it varies between individuals; however, they do have prolonged or delayed bleeding after relatively minor trauma and are usually diagnosed before age five to six years; the frequency of bleeding episodes varies, usually from once a month to once a year. Individuals with mild hemophilia A do not have spontaneous bleeding episodes; however, without pre- and postoperative treatment, abnormal bleeding occurs with surgery or tooth extractions; the frequency of bleeding episodes varies widely, typically from once a year to once every ten years. Individuals with mild hemophilia A are often not diagnosed until later in life. Approximately 30% of heterozygous females have factor VIII clotting activity below 40% and are at risk for bleeding (even if males in the family are only mildly affected). After major trauma or invasive procedures, prolonged or excessive bleeding usually occurs, regardless of severity. In addition, 25% of heterozygous females with normal factor VIII clotting activity report an increased bleeding tendency.
Storage pool disease of platelets
MedGen UID:
19351
Concept ID:
C0032197
Disease or Syndrome
A rare hemorrhagic disorder due to a constitutional platelet anomaly characterized by moderate to severe deficiency in both platelet alpha-granules and dense bodies, resulting in impaired platelet function and decreased aggregation responses. Patients present increased bleeding tendency with symptoms like easy bruising, or menorrhagia.
Neonatal hemochromatosis
MedGen UID:
82768
Concept ID:
C0268059
Disease or Syndrome
Neonatal hemochromatosis (NH) is characterized by hepatic failure in the newborn period and heavy iron staining in the liver. In addition, there is marked siderosis of extrahepatic tissues, including the heart and pancreas (Driscoll et al., 1988). Whitington (2007) postulated that some cases of neonatal hemochromatosis result from maternal alloimmunity directed at the fetal liver, and therefore do not represent an inherited mendelian disorder. Other causes may result from metabolic disease or perinatal infection. In particular, he commented that the disorder is not related to the family of inherited liver diseases that fall under the classification of hereditary hemochromatosis (see, e.g., 235200). Whitington (2007) proposed the term 'congenital alloimmune hepatitis.' In the past, the disorder has loosely been labeled 'neonatal hepatitis' and 'giant cell hepatitis,' which are pathologic findings in the liver representing a common response to a variety of insults, including cholestatic disorders and infection, among others (Fawaz et al., 1975; Knisely et al., 1987; Kelly et al., 2001).
Gray platelet syndrome
MedGen UID:
82900
Concept ID:
C0272302
Disease or Syndrome
The gray platelet syndrome (GPS) is a rare inherited disorder characterized by mild to moderate bleeding tendency, moderate thrombocytopenia, and a marked decrease or absence of platelet alpha-granules and of the proteins contained in alpha-granules. The platelets are enlarged, but not giant, and have a gray appearance on light microscopy of Wright-stained peripheral blood smears due to decreased granules. Many patients with gray platelet syndrome develop a stable myelofibrosis (summary by Nurden and Nurden, 2007). Cases suggesting autosomal dominant and autosomal recessive inheritance have been described, indicating that GPS is probably a genetically heterogeneous disorder with more than one molecular cause.
Congenital factor VII deficiency
MedGen UID:
473015
Concept ID:
C0272320
Disease or Syndrome
A rare, genetic, congenital vitamin K-dependant coagulation factor deficiency disorder characterized by decreased levels or absence of coagulation factor VII (FVII), resulting in bleeding diathesis of variable severity.
Autoimmune thrombocytopenic purpura
MedGen UID:
584986
Concept ID:
C0398650
Disease or Syndrome
Immune thrombocytopenic purpura is characterized by a low platelet count, normal bone marrow, and the absence of other causes of thrombocytopenia. It is principally a disorder of increased platelet destruction mediated by autoantibodies to platelet-membrane antigens (George et al., 1994).
SCOTT SYNDROME
MedGen UID:
167107
Concept ID:
C0796149
Disease or Syndrome
Scott syndrome (SCTS) is a mild platelet-type bleeding disorder characterized by impaired surface exposure of procoagulant phosphatidylserine (PS) on platelets and other blood cells, following activation with Ca(2+)-elevating agents (Munnix et al., 2003).
von Willebrand disease type 3
MedGen UID:
266075
Concept ID:
C1264041
Disease or Syndrome
Von Willebrand disease (VWD), a congenital bleeding disorder caused by deficient or defective plasma von Willebrand factor (VWF), may only become apparent on hemostatic challenge, and bleeding history may become more apparent with increasing age. Recent guidelines on VWD have recommended taking a VWF level of 30 or 40 IU/dL as a cutoff for those diagnosed with the disorder. Individuals with VWF levels greater than 30 IU/dL and lower than 50 IU/dL can be described as having a risk factor for bleeding. This change in guidelines significantly alters the proportion of individuals with each disease type. Type 1 VWD (~30% of VWD) typically manifests as mild mucocutaneous bleeding. Type 2 VWD accounts for approximately 60% of VWD. Type 2 subtypes include: Type 2A, which usually manifests as mild-to-moderate mucocutaneous bleeding; Type 2B, which typically manifests as mild-to-moderate mucocutaneous bleeding that can include thrombocytopenia that worsens in certain circumstances; Type 2M, which typically manifests as mild-moderate mucocutaneous bleeding; Type 2N, which can manifest as excessive bleeding with surgery and mimics mild hemophilia A. Type 3 VWD (<10% of VWD) manifests with severe mucocutaneous and musculoskeletal bleeding.
Body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency
MedGen UID:
332067
Concept ID:
C1835813
Disease or Syndrome
Body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency is a very rare genetic skin disease characterized by severe skin laxity affecting the trunk and limbs.
Von Willebrand disease, X-linked form
MedGen UID:
333255
Concept ID:
C1839113
Disease or Syndrome
Thrombocytopenia with elevated serum IgA and renal disease
MedGen UID:
374149
Concept ID:
C1839162
Disease or Syndrome
Platelet-type bleeding disorder 10
MedGen UID:
374856
Concept ID:
C1842090
Disease or Syndrome
Any inherited bleeding disorder, platelet-type in which the cause of the disease is a mutation in the CD36 gene.
Vitamin K-dependent clotting factors, combined deficiency of, type 2
MedGen UID:
334505
Concept ID:
C1843832
Disease or Syndrome
Deficiency of all vitamin K-dependent clotting factors leads to a bleeding tendency that is usually reversed by oral administration of vitamin K. Familial multiple coagulation factor deficiency is rare. Clinical symptoms of the disease include episodes of intracranial hemorrhage in the first weeks of life, sometimes leading to a fatal outcome (Fregin et al., 2002). For a general phenotypic description and a discussion of genetic heterogeneity of combined deficiency of vitamin K-dependent clotting factors, see VKCFD1 (277450).
Vitamin K-dependent clotting factors, combined deficiency of, type 1
MedGen UID:
376381
Concept ID:
C1848534
Disease or Syndrome
Deficiency of all vitamin K-dependent clotting factors leads to a bleeding tendency that is usually reversed by oral administration of vitamin K. Acquired forms of the disorder can be caused by intestinal malabsorption of vitamin K. Familial multiple coagulation factor deficiency is rare. Clinical symptoms of the disease include episodes of intracranial hemorrhage in the first weeks of life, sometimes leading to a fatal outcome. The pathomechanism is based on a reduced hepatic gamma-carboxylation of glutamic acid residues of all vitamin K-dependent blood coagulation factors, as well as the anticoagulant factors protein C (612283) and protein S (176880). Posttranslational gamma-carboxylation of proteins enables the calcium-dependent attachment of the proteins to the phospholipid bilayer of membranes, an essential prerequisite for blood coagulation. Vitamin K1 acts as a cofactor for the vitamin K-dependent carboxylase in liver microsomes, GGCX. Genetic Heterogeneity of Combined Deficiency of Vitamin K-Dependent Clotting Factors Combined deficiency of vitamin K-dependent clotting factors-2 (VKFCD2; 607473) is caused by mutation in the gene encoding vitamin K epoxide reductase (VKORC1; 608547) on chromosome 16p11.
Tatsumi factor deficiency
MedGen UID:
336460
Concept ID:
C1848931
Disease or Syndrome
Noonan syndrome 4
MedGen UID:
339908
Concept ID:
C1853120
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Platelet-type bleeding disorder 8
MedGen UID:
344008
Concept ID:
C1853278
Disease or Syndrome
Platelet-type bleeding disorder-8 (BDPLT8) is an autosomal recessive condition characterized by mild to moderate mucocutaneous bleeding and excessive bleeding after surgery or trauma. The defect is due to the inability of ADP to induce platelet aggregation (review by Cattaneo, 2011).
Factor V and factor VIII, combined deficiency of, with normal protein C and protein C inhibitor
MedGen UID:
346462
Concept ID:
C1856882
Disease or Syndrome
Wolfram syndrome 2
MedGen UID:
347604
Concept ID:
C1858028
Disease or Syndrome
Wolfram syndrome-2 (WFS2) is an autosomal recessive neurodegenerative disorder characterized by diabetes mellitus, high frequency sensorineural hearing loss, optic atrophy or neuropathy, and defective platelet aggregation resulting in peptic ulcer bleeding (summary by Mozzillo et al., 2014). For a discussion of genetic heterogeneity of Wolfram syndrome, see WFS1 (222300).
Athrombia, essential
MedGen UID:
349197
Concept ID:
C1859595
Disease or Syndrome
Arthrogryposis, renal dysfunction, and cholestasis 1
MedGen UID:
347219
Concept ID:
C1859722
Disease or Syndrome
Any arthrogryposis-renal dysfunction-cholestasis syndrome in which the cause of the disease is a mutation in the VPS33B gene.
Aplasia cutis congenita-intestinal lymphangiectasia syndrome
MedGen UID:
349241
Concept ID:
C1859753
Disease or Syndrome
An extremely rare association syndrome, described in only two brothers to date (one of which died at 2 months of age), characterized by aplasia cutis congenita of the vertex and generalized edema (as well as hypoproteinemia and lymphopenia) due to intestinal lymphangiectasia. There have been no further descriptions in the literature since 1985.
Antithrombin, familial hemorrhagic diathesis due to
MedGen UID:
347227
Concept ID:
C1859761
Disease or Syndrome
Platelet-type bleeding disorder 17
MedGen UID:
396078
Concept ID:
C1861194
Disease or Syndrome
Platelet-type bleeding disorder-17 is an autosomal dominant disorder characterized by increased bleeding tendency due to abnormal platelet function. It is a type of 'gray platelet syndrome' because the platelets appear abnormal on light microscopy. Electron microscopy shows decreased or absent alpha-granules within platelets, and bone marrow biopsy shows increased numbers of abnormal megakaryocytes, suggesting a defect in megakaryopoiesis and platelet production. The bleeding severity is variable (summary by Monteferrario et al., 2014).
Stormorken syndrome
MedGen UID:
350028
Concept ID:
C1861451
Disease or Syndrome
Stormorken syndrome is an autosomal dominant disorder characterized by mild bleeding tendency due to platelet dysfunction, thrombocytopenia, anemia, asplenia, tubular aggregate myopathy, congenital miosis, and ichthyosis. Additional features may include headache or recurrent stroke-like episodes (summary by Misceo et al., 2014).
Car factor deficiency
MedGen UID:
354615
Concept ID:
C1861898
Disease or Syndrome
MPI-congenital disorder of glycosylation
MedGen UID:
400692
Concept ID:
C1865145
Disease or Syndrome
Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans or oligosaccharides on glycoproteins. Type I CDGs comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (LLO) chain and its transfer to the nascent protein. These disorders can be identified by a characteristic abnormal isoelectric focusing profile of plasma transferrin (Leroy, 2006). For a discussion of the classification of CDGs, see CDG1A (212065). CDG Ib is clinically distinct from most other CDGs by the lack of significant central nervous system involvement. The predominant symptoms are chronic diarrhea with failure to thrive and protein-losing enteropathy with coagulopathy. Some patients develop hepatic fibrosis. CDG Ib is also different from other CDGs in that it can be treated effectively with oral mannose supplementation, but can be fatal if untreated (Marquardt and Denecke, 2003). Thus, CDG Ib should be considered in the differential diagnosis of patients with unexplained hypoglycemia, chronic diarrhea, liver disease, or coagulopathy in order to allow early diagnosis and effective therapy (Vuillaumier-Barrot et al., 2002) Freeze and Aebi (1999) reviewed CDG Ib and CDG Ic (603147). Marques-da-Silva et al. (2017) systematically reviewed the literature concerning liver involvement in CDG.
Primary release disorder of platelets
MedGen UID:
356845
Concept ID:
C1867770
Disease or Syndrome
Platelet signal processing defect
MedGen UID:
357448
Concept ID:
C1868199
Disease or Syndrome
Platelet factor 3 deficiency
MedGen UID:
356931
Concept ID:
C1868256
Disease or Syndrome
Platelet disorder, undefined
MedGen UID:
401405
Concept ID:
C1868258
Disease or Syndrome
Pechet factor deficiency
MedGen UID:
358349
Concept ID:
C1868545
Disease or Syndrome
Paris-Trousseau thrombocytopenia
MedGen UID:
365037
Concept ID:
C1956093
Disease or Syndrome
Paris-Trousseau thrombocytopenia (TCPT) is a contiguous gene syndrome characterized by mild bleeding tendency, variable thrombocytopenia (THC), dysmorphic facies, abnormal giant alpha-granules in platelets and dysmegakaryopoiesis.
Congenital afibrinogenemia
MedGen UID:
749036
Concept ID:
C2584774
Disease or Syndrome
Inherited disorders of fibrinogen affect either the quantity (afibrinogenemia and hypofibrinogenemia; 202400) or the quality (dysfibrinogenemia; 616004) of the circulating fibrinogen or both (hypodysfibrinogenemia; see 616004). Afibrinogenemia is characterized by the complete absence of immunoreactive fibrinogen. Bleeding due to afibrinogenemia usually manifests in the neonatal period, with 85% of cases presenting umbilical cord bleeding, but a later age of onst is not unusual. Bleeding may occur in the skin, gastrointestinal tract, genitourinary tract, or the central nervous system, with intracranial hemorrhage being reported as the major cause of death. Patients are susceptible to spontaneous rupture of the spleen. Menstruating women may experience menometrorrhagia. First-trimester abortion is common. Both arterial and venous thromboembolic complications have been reported (summary by de Moerloose and Neerman-Arbez, 2009). Hypofibrinogenemia is characterized by reduced amounts of immunoreactive fibrinogen. Patients are often heterozygous carriers of afibrinogenemia mutations and are usually asymptomatic. However, they may bleed when exposed to trauma or if they have a second associated hemostatic abnormality. Women may experience miscarriages. Liver disease occurs in rare cases (summary by de Moerloose and Neerman-Arbez, 2009).
Leukocyte adhesion deficiency 3
MedGen UID:
411605
Concept ID:
C2748536
Disease or Syndrome
Leukocyte adhesion deficiency-3 (LAD3), also known as LAD1 variant (LAD1V), is an autosomal recessive disorder characterized by LAD1 (116920)-like immune deficiency and Glanzmann thrombasthenia (GT; 273800)-like bleeding problems. LAD3 results from mutations in FERMT3, or KINDLIN3, which encodes an intracellular protein that interacts with beta-integrins in hematopoietic cells. In LAD3, the adhesive functions of integrins on both leukocytes and platelets are disrupted, most likely due to defects in activation-dependent alterations of surface integrins that enable high-avidity binding to ligands on target cells, a process termed 'inside-out signaling' (Svensson et al., 2009; Zimmerman, 2009). For a discussion of genetic heterogeneity of leukocyte adhesion deficiency, see 116920.
Sitosterolemia 1
MedGen UID:
440869
Concept ID:
C2749759
Disease or Syndrome
Sitosterolemia is characterized by: Hypercholesterolemia (especially in children) which (1) shows an unexpected significant lowering of plasma cholesterol level in response to low-fat diet modification or to bile acid sequestrant therapy; or (2) does not respond to statin therapy; Tendon xanthomas or tuberous (i.e., planar) xanthomas that can occur in childhood and in unusual locations (heels, knees, elbows, and buttocks); Premature atherosclerosis, which can lead to angina, aortic valve involvement, myocardial infarction, and sudden death; Hemolytic anemia, abnormally shaped erythrocytes (stomatocytes), and large platelets (macrothrombocytopenia). On occasion, the abnormal hematologic findings may be the initial presentation or the only clinical feature of this disorder. Arthritis, arthralgias, and splenomegaly may sometimes be seen and one study has concluded that "idiopathic" liver disease could be undiagnosed sitosterolemia. The clinical spectrum of sitosterolemia is probably not fully appreciated due to underdiagnosis and the fact that the phenotype in infants is likely to be highly dependent on diet.
Congenital plasminogen activator inhibitor type 1 deficiency
MedGen UID:
412870
Concept ID:
C2750067
Disease or Syndrome
Untreated complete plasminogen activator inhibitor 1 (PAI-1) deficiency is characterized by mild-to-moderate bleeding, although in some instances bleeding can be life threatening. Most commonly, delayed bleeding is associated with injury, trauma, or surgery; spontaneous bleeding does not occur. While males and females with complete PAI-1 deficiency are affected equally, females may present more frequently with clinical manifestations or earlier in life than males due to menorrhagia and postpartum hemorrhage. Fewer than ten families with complete PAI-1 deficiency have been reported to date. The incidence of complete PAI-1 deficiency is higher than expected in the genetic isolate of the Old Order Amish population of eastern and southern Indiana due to a pathogenic founder variant. In one family from this Old Order Amish population, seven individuals had cardiac fibrosis ranging from minimal-to-moderate (6 individuals) to severe (1).
Factor XIII, b subunit, deficiency of
MedGen UID:
442490
Concept ID:
C2750481
Finding
Factor XIII deficiency is an autosomal recessive hematologic disorder characterized by increased bleeding and poor wound healing. Most cases of congenital factor XIII deficiency result from mutation in the A subunit (Kangsadalampai et al., 1999). Ichinose et al. (1996, 2000) proposed a classification of factor XIII deficiency: XIIIA deficiency (formerly 'type II' F13 deficiency) and XIIIB deficiency (formerly 'type I' F13 deficiency), as well as a possible combined deficiency of the 2.
Factor XIII, A subunit, deficiency of
MedGen UID:
442497
Concept ID:
C2750514
Disease or Syndrome
Factor XIII deficiency is an autosomal recessive hematologic disorder characterized by increased bleeding and poor wound healing. Most cases of congenital factor XIII deficiency result from mutation in the A subunit (Kangsadalampai et al., 1999). Ichinose et al. (1996, 2000) proposed a classification of factor XIII deficiency: XIIIA deficiency (formerly 'type II' F13 deficiency) and XIIIB deficiency (formerly 'type I' F13 deficiency), as well as a possible combined deficiency of the 2.
Glycogen storage disease due to glucose-6-phosphatase deficiency type IA
MedGen UID:
415885
Concept ID:
C2919796
Disease or Syndrome
Glycogen storage disease type I (GSDI) is characterized by accumulation of glycogen and fat in the liver and kidneys resulting in hepatomegaly and nephromegaly. Severely affected infants present in the neonatal period with severe hypoglycemia due to fasting intolerance. More commonly, untreated infants present at age three to four months with hepatomegaly, severe hypoglycemia with or without seizures, lactic acidosis, hyperuricemia, and hypertriglyceridemia. Affected children typically have doll-like faces with full cheeks, relatively thin extremities, short stature, and a protuberant abdomen. Xanthoma and diarrhea may be present. Impaired platelet function and development of reduced or dysfunctional von Willebrand factor can lead to a bleeding tendency with frequent epistaxis and menorrhagia in females. Individuals with untreated GSDIb are more likely to develop impaired neutrophil and monocyte function as well as chronic neutropenia resulting in recurrent bacterial infections, gingivitis, periodontitis, and genital and intestinal ulcers. Long-term complications of untreated GSDI include short stature, osteoporosis, delayed puberty, renal disease (including proximal and distal renal tubular acidosis, renal stones, and renal failure), gout, systemic hypertension, pulmonary hypertension, hepatic adenomas with potential for malignancy, pancreatitis, and polycystic ovaries. Seizures and cognitive impairment may occur in individuals with prolonged periods of hypoglycemia. Normal growth and puberty are expected in treated children. Most affected individuals live into adulthood.
Hemorrhagic disorder due to hyperheparinemia
MedGen UID:
469019
Concept ID:
C3203346
Disease or Syndrome
Hermansky-Pudlak syndrome 4
MedGen UID:
483344
Concept ID:
C3484357
Disease or Syndrome
Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. Ocular findings include reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. The bleeding diathesis can result in variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and can progress to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. Neutropenia and/or immune defects occur primarily in individuals with pathogenic variants in AP3B1 and AP3D1.
Peroxisome biogenesis disorder type 3B
MedGen UID:
763607
Concept ID:
C3550693
Disease or Syndrome
Zellweger spectrum disorder (ZSD) is a phenotypic continuum ranging from severe to mild. While individual phenotypes (e.g., Zellweger syndrome [ZS], neonatal adrenoleukodystrophy [NALD], and infantile Refsum disease [IRD]) were described in the past before the biochemical and molecular bases of this spectrum were fully determined, the term "ZSD" is now used to refer to all individuals with a defect in one of the ZSD-PEX genes regardless of phenotype. Individuals with ZSD usually come to clinical attention in the newborn period or later in childhood. Affected newborns are hypotonic and feed poorly. They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling [chondrodysplasia punctata] of the patella[e] and the long bones), and liver disease that can be severe. Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress. Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia, polyneuropathy, and leukodystrophy), liver dysfunction, adrenal insufficiency, and renal oxalate stones. While hypotonia and developmental delays are typical, intellect can be normal. Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth.
COG6-ongenital disorder of glycosylation
MedGen UID:
766144
Concept ID:
C3553230
Disease or Syndrome
CDG2L is an autosomal recessive multisystem disorder apparent from birth or early infancy. It is characterized by poor growth, gastrointestinal and liver abnormalities, delayed psychomotor development, hypotonia, recurrent infections, hematologic abnormalities, increased bleeding tendency, and hyperhidrosis or hyperkeratosis. More variable features include nonspecific dysmorphic facial features and cardiac septal defects. The disorder often results in death in infancy or the first years of life (summary by Rymen et al., 2015). For a general discussion of CDGs, see CDG1A (212065) and CDG2A (212066).
Hermansky-Pudlak syndrome 3
MedGen UID:
854708
Concept ID:
C3888001
Disease or Syndrome
Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. Ocular findings include reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. The bleeding diathesis can result in variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and can progress to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. Neutropenia and/or immune defects occur primarily in individuals with pathogenic variants in AP3B1 and AP3D1.
Platelet-type bleeding disorder 19
MedGen UID:
863842
Concept ID:
C4015405
Disease or Syndrome
A rare isolated hereditary giant platelet disorder characterized by severe thrombocytopenia and thrombopathy due to defects in proplatelet formation and platelet activation in homozygous patients. Clinical manifestation are recurrent bleeding episodes including epistaxis, spontaneous hematomas, and menorrhagia.
Thrombocytopenia 6
MedGen UID:
934756
Concept ID:
C4310789
Disease or Syndrome
Thrombocytopenia-6 is an autosomal dominant hematologic disorder characterized by increased bleeding episodes due to reduced platelet count and abnormal platelet morphology resulting from defective megakaryopoiesis. Patients may also have bone abnormalities, including osteoporosis or tooth loss, as well as an increased risk for myelofibrosis (summary by Turro et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of thrombocytopenia, see 313900.
Developmental and epileptic encephalopathy, 36
MedGen UID:
1382656
Concept ID:
C4317295
Disease or Syndrome
Developmental and epileptic encephalopathy-36 (DEE36) is an X-linked neurodevelopmental disorder characterized by the onset of seizures at a mean age of 6.5 months. Most patients present with infantile spasms associated with hypsarrhythmia on EEG, consistent with a clinical diagnosis of West syndrome. The seizures tend to be refractory to treatment, although some patients may respond to benzodiazepines or a ketogenic diet. Affected individuals have severely delayed psychomotor development with poor motor function, severe intellectual disability, poor or absent speech, and limited eye contact. More variable features include feeding difficulties sometimes requiring tube feeding, ocular defects including cortical visual impairment, dysmorphic facial features, and scoliosis or osteopenia. The vast majority of patients reported have been females, although rare affected males with a similar phenotype have been described. Most patients show normal N-glycosylation on transferrin isoelectric focusing, but some show abnormal N-glycosylation consistent with CDG type I (summary by Ng et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350. For a discussion of the classification of CDGs, see CDG1A (212065).
Bleeding disorder, platelet-type, 21
MedGen UID:
1386863
Concept ID:
C4479515
Disease or Syndrome
BDPLT21 is a hematologic disorder characterized by increased risk of bleeding resulting from a functional platelet defect. Platelets have decreased or even absent dense bodies and abnormally enlarged and fused alpha-granules, and they show defective secretion and aggregation responses to agonists. Platelets are usually enlarged, and some patients may have mild to moderate thrombocytopenia (summary by Saultier et al., 2017).
Noonan syndrome 1
MedGen UID:
1638960
Concept ID:
C4551602
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Factor V and factor VIII, combined deficiency of, type 1
MedGen UID:
1637212
Concept ID:
C4551981
Disease or Syndrome
Combined deficiency of factor V and factor VIII (F5F8D1) is characterized by bleeding symptoms similar to those in hemophilia (306700) or parahemophilia (227400), caused by single deficiency of factor V (612309) or factor VIII (300840), respectively. The most common symptoms are epistaxis, menorrhagia, and excessive bleeding during or after trauma. Plasma FV and FVIII antigen and activity levels are in the range of 5 to 30%. Inheritance of F5F8D is autosomal recessive and distinct from the coinheritance of FV deficiency and FVIII deficiency (summary by Zhang and Ginsburg, 2004). Genetic Heterogeneity of Combined Deficiency of Factor V and Factor VIII Another form of combined deficiency of factor V and factor VIII (F5F8D2; 613625) is caused by mutation in the MCFD2 gene (607788) on chromosome 2p21.
Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss
MedGen UID:
1704278
Concept ID:
C5200934
Disease or Syndrome
MYH9-related disease (MYH9-RD) is characterized in all affected individuals by hematologic features present from birth consisting of platelet macrocytosis (i.e., >40% of platelets larger than 3.9 µm in diameter), thrombocytopenia (platelet count <150 x 109/L), and aggregates of the MYH9 protein in the cytoplasm of neutrophil granulocytes. Most affected individuals develop one or more additional extrahematologic manifestations of the disease over their lifetime, including sensorineural hearing loss, renal disease (manifesting initially as glomerular nephropathy), presenile cataracts, and/or elevation of liver enzymes.
Platelet-type bleeding disorder 16
MedGen UID:
1781222
Concept ID:
C5442010
Disease or Syndrome
Platelet-type bleeding disorder-16 (BDPLT16) is an autosomal dominant form of congenital macrothrombocytopenia associated with platelet anisocytosis. It is a disorder of platelet production. Affected individuals may have no or only mildly increased bleeding tendency. In vitro studies show mild platelet functional abnormalities (summary by Kunishima et al., 2011 and Nurden et al., 2011). Genetic Heterogeneity of Glanzmann Thrombasthenia-like with Macrothromocytopenia See BDPLT24 (619271), caused by mutation in the ITGB3 gene (173470) on chromosome 17q21.32. Together the ITGB2B and ITBG3 genes form an integrin, known as platelet glycoprotein GPIIb/III, that is expressed on platelets.
Glanzmann thrombasthenia 2
MedGen UID:
1782592
Concept ID:
C5543273
Disease or Syndrome
Glanzmann thrombasthenia-2 (GT2) is an autosomal recessive bleeding disorder characterized by failure of platelet aggregation and by absent or diminished clot retraction. The abnormalities are related to quantitative or qualitative abnormalities of the GPIIb (607759)/IIIa platelet surface fibrinogen receptor complex resulting from mutations in the GPIIIa gene (Rosenberg et al., 1997). For a general phenotypic description and a discussion of genetic heterogeneity of Glanzmann thrombasthenia, see 273800.
Bleeding disorder, platelet-type, 24
MedGen UID:
1785711
Concept ID:
C5543280
Disease or Syndrome
Platelet-type bleeding disorder-24 (BDPLT24) is an autosomal dominant form of congenital macrothrombocytopenia associated with platelet anisocytosis. It is a disorder of platelet production. Affected individuals may have no or only mildly increased bleeding tendency. In vitro studies show mild platelet functional abnormalities (summary by Kunishima et al., 2011 and Nurden et al., 2011). For a discussion of genetic heterogeneity of Glanzmann thrombasthenia-like with macrothrombocytopenia, see 187800.
3-methylglutaconic aciduria, type VIIB
MedGen UID:
1810214
Concept ID:
C5676893
Disease or Syndrome
CLPB (caseinolytic peptidase B) deficiency is characterized by neurologic involvement and neutropenia, which can range from severe to mild. In severe CLPB deficiency, death usually occurs at a few months of age due to significant neonatal neurologic involvement (hyperekplexia or absence of voluntary movements, hypotonia or hypertonia, swallowing problems, respiratory insufficiency, and epilepsy) and severe neutropenia associated with life-threatening infections. Individuals with moderate CLPB deficiency present with neurologic abnormalities in infancy including hypotonia and feeding problems, and develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability. Neutropenia is variable, but not life threatening. In those with mild CLPB deficiency there is no neurologic involvement, intellect is normal, neutropenia is mild and intermittent, and life expectancy is normal.
Inherited prekallikrein deficiency
MedGen UID:
987194
Concept ID:
CN305372
Disease or Syndrome
Prekallikrein deficiency (PKKD) is a rare asymptomatic clotting defect characterized by prolongation of activated partial thromboplastin time (summary by Saito et al., 1981).

Professional guidelines

PubMed

Vitale SG, Buzzaccarini G, Riemma G, Pacheco LA, Di Spiezio Sardo A, Carugno J, Chiantera V, Török P, Noventa M, Haimovich S, De Franciscis P, Perez-Medina T, Angioni S, Laganà AS
J Gynecol Obstet Hum Reprod 2023 Jun;52(6):102588. Epub 2023 Apr 13 doi: 10.1016/j.jogoh.2023.102588. PMID: 37061093
Marnach ML, Laughlin-Tommaso SK
Mayo Clin Proc 2019 Feb;94(2):326-335. doi: 10.1016/j.mayocp.2018.12.012. PMID: 30711128
Donnez J, Dolmans MM
Hum Reprod Update 2016 Nov;22(6):665-686. Epub 2016 Jul 27 doi: 10.1093/humupd/dmw023. PMID: 27466209Free PMC Article

Recent clinical studies

Etiology

Ring KL, Mills AM, Modesitt SC
Obstet Gynecol 2022 Dec 1;140(6):1061-1075. Epub 2022 Nov 2 doi: 10.1097/AOG.0000000000004989. PMID: 36357974
Lee A, Syed YY
Drugs 2022 Jul;82(10):1117-1125. Epub 2022 Jul 4 doi: 10.1007/s40265-022-01738-8. PMID: 35781795Free PMC Article
D'Alton ME, Rood KM, Smid MC, Simhan HN, Skupski DW, Subramaniam A, Gibson KS, Rosen T, Clark SM, Dudley D, Iqbal SN, Paglia MJ, Duzyj CM, Chien EK, Gibbins KJ, Wine KD, Bentum NAA, Kominiarek MA, Tuuli MG, Goffman D
Obstet Gynecol 2020 Nov;136(5):882-891. doi: 10.1097/AOG.0000000000004138. PMID: 32909970Free PMC Article
Donnez J, Dolmans MM
Hum Reprod Update 2016 Nov;22(6):665-686. Epub 2016 Jul 27 doi: 10.1093/humupd/dmw023. PMID: 27466209Free PMC Article
Andrade C, Sandarsh S, Chethan KB, Nagesh KS
J Clin Psychiatry 2010 Dec;71(12):1565-75. doi: 10.4088/JCP.09r05786blu. PMID: 21190637

Diagnosis

Vitale SG, Buzzaccarini G, Riemma G, Pacheco LA, Di Spiezio Sardo A, Carugno J, Chiantera V, Török P, Noventa M, Haimovich S, De Franciscis P, Perez-Medina T, Angioni S, Laganà AS
J Gynecol Obstet Hum Reprod 2023 Jun;52(6):102588. Epub 2023 Apr 13 doi: 10.1016/j.jogoh.2023.102588. PMID: 37061093
Hofer S, Blaha J, Collins PW, Ducloy-Bouthors AS, Guasch E, Labate F, Lança F, Nyfløt LT, Steiner K, Van de Velde M
Eur J Anaesthesiol 2023 Jan 1;40(1):29-38. Epub 2022 Sep 22 doi: 10.1097/EJA.0000000000001744. PMID: 36131564Free PMC Article
Ring KL, Mills AM, Modesitt SC
Obstet Gynecol 2022 Dec 1;140(6):1061-1075. Epub 2022 Nov 2 doi: 10.1097/AOG.0000000000004989. PMID: 36357974
Marnach ML, Laughlin-Tommaso SK
Mayo Clin Proc 2019 Feb;94(2):326-335. doi: 10.1016/j.mayocp.2018.12.012. PMID: 30711128
Munro MG, Critchley HOD, Fraser IS; FIGO Menstrual Disorders Committee
Int J Gynaecol Obstet 2018 Dec;143(3):393-408. Epub 2018 Oct 10 doi: 10.1002/ijgo.12666. PMID: 30198563

Therapy

Hofer S, Blaha J, Collins PW, Ducloy-Bouthors AS, Guasch E, Labate F, Lança F, Nyfløt LT, Steiner K, Van de Velde M
Eur J Anaesthesiol 2023 Jan 1;40(1):29-38. Epub 2022 Sep 22 doi: 10.1097/EJA.0000000000001744. PMID: 36131564Free PMC Article
Lee A, Syed YY
Drugs 2022 Jul;82(10):1117-1125. Epub 2022 Jul 4 doi: 10.1007/s40265-022-01738-8. PMID: 35781795Free PMC Article
D'Alton ME, Rood KM, Smid MC, Simhan HN, Skupski DW, Subramaniam A, Gibson KS, Rosen T, Clark SM, Dudley D, Iqbal SN, Paglia MJ, Duzyj CM, Chien EK, Gibbins KJ, Wine KD, Bentum NAA, Kominiarek MA, Tuuli MG, Goffman D
Obstet Gynecol 2020 Nov;136(5):882-891. doi: 10.1097/AOG.0000000000004138. PMID: 32909970Free PMC Article
Donnez J, Dolmans MM
Hum Reprod Update 2016 Nov;22(6):665-686. Epub 2016 Jul 27 doi: 10.1093/humupd/dmw023. PMID: 27466209Free PMC Article
Andrade C, Sandarsh S, Chethan KB, Nagesh KS
J Clin Psychiatry 2010 Dec;71(12):1565-75. doi: 10.4088/JCP.09r05786blu. PMID: 21190637

Prognosis

Hill S, Shetty MK
Semin Ultrasound CT MR 2023 Dec;44(6):511-518. Epub 2023 Oct 11 doi: 10.1053/j.sult.2023.10.002. PMID: 37832698
Lee A, Syed YY
Drugs 2022 Jul;82(10):1117-1125. Epub 2022 Jul 4 doi: 10.1007/s40265-022-01738-8. PMID: 35781795Free PMC Article
Clarke MA, Long BJ, Sherman ME, Lemens MA, Podratz KC, Hopkins MR, Ahlberg LJ, Mc Guire LJ, Laughlin-Tommaso SK, Bakkum-Gamez JN, Wentzensen N
Am J Obstet Gynecol 2020 Oct;223(4):549.e1-549.e13. Epub 2020 Apr 5 doi: 10.1016/j.ajog.2020.03.032. PMID: 32268124Free PMC Article
Piessens S, Edwards A
J Minim Invasive Gynecol 2020 Feb;27(2):265-266. Epub 2019 Sep 4 doi: 10.1016/j.jmig.2019.08.027. PMID: 31493569
Marnach ML, Laughlin-Tommaso SK
Mayo Clin Proc 2019 Feb;94(2):326-335. doi: 10.1016/j.mayocp.2018.12.012. PMID: 30711128

Clinical prediction guides

Christie CDC, Lue AM, Melbourne-Chambers RH
Curr Opin Pediatr 2023 Apr 1;35(2):155-165. Epub 2023 Feb 22 doi: 10.1097/MOP.0000000000001229. PMID: 36801979Free PMC Article
Lee A, Syed YY
Drugs 2022 Jul;82(10):1117-1125. Epub 2022 Jul 4 doi: 10.1007/s40265-022-01738-8. PMID: 35781795Free PMC Article
D'Alton ME, Rood KM, Smid MC, Simhan HN, Skupski DW, Subramaniam A, Gibson KS, Rosen T, Clark SM, Dudley D, Iqbal SN, Paglia MJ, Duzyj CM, Chien EK, Gibbins KJ, Wine KD, Bentum NAA, Kominiarek MA, Tuuli MG, Goffman D
Obstet Gynecol 2020 Nov;136(5):882-891. doi: 10.1097/AOG.0000000000004138. PMID: 32909970Free PMC Article
Clarke MA, Long BJ, Sherman ME, Lemens MA, Podratz KC, Hopkins MR, Ahlberg LJ, Mc Guire LJ, Laughlin-Tommaso SK, Bakkum-Gamez JN, Wentzensen N
Am J Obstet Gynecol 2020 Oct;223(4):549.e1-549.e13. Epub 2020 Apr 5 doi: 10.1016/j.ajog.2020.03.032. PMID: 32268124Free PMC Article
Piessens S, Edwards A
J Minim Invasive Gynecol 2020 Feb;27(2):265-266. Epub 2019 Sep 4 doi: 10.1016/j.jmig.2019.08.027. PMID: 31493569

Recent systematic reviews

Mahdanian AA, Rej S, Bacon SL, Ozdin D, Lavoie KL, Looper K
Expert Opin Drug Saf 2014 Jun;13(6):695-704. Epub 2014 Apr 9 doi: 10.1517/14740338.2014.908182. PMID: 24717049
Abdel-Aleem H, d'Arcangues C, Vogelsong KM, Gaffield ML, Gülmezoglu AM
Cochrane Database Syst Rev 2013 Oct 21;(10):CD003449. doi: 10.1002/14651858.CD003449.pub5. PMID: 24146298
Abdel-Aleem H, d'Arcangues C, Vogelsong KM, Gaffield ML, Gülmezoglu AM
Cochrane Database Syst Rev 2013 Jul 2;(7):CD003449. doi: 10.1002/14651858.CD003449.pub4. PMID: 23828544
Ely JW, Kennedy CM, Clark EC, Bowdler NC
J Am Board Fam Med 2006 Nov-Dec;19(6):590-602. doi: 10.3122/jabfm.19.6.590. PMID: 17090792
Gentile GP, Kaufman SC, Helbig DW
Fertil Steril 1998 Feb;69(2):179-86. doi: 10.1016/s0015-0282(97)00229-x. PMID: 9496325

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